Indolin phenylsulfonamide derivatives

ABSTRACT

The invention relates to novel substituted indolin phenylsulfonamide derivatives, to a method for the production thereof and to the use thereof in medicaments, especially as potent PPAR-delta activating compounds for the prophylaxis and/or treatment of cardiovascular diseases, especially dyslipidaemia and coronary heart diseases.

The present application relates to novel substitutedindolinephenylsulphonamide derivatives, to processes for theirpreparation and to their use in medicaments, in particular as potentPPAR-delta-activating compounds for the prophylaxis and/or treatment ofcardiovascular disorders, in particular dyslipidaemias, arteriosclerosisand coronary heart diseases.

In spite of many successful therapies, coronary heart diseases (CHDs)remain a serious public health problem. Treatment with statins, whichinhibit HMG-CoA reductase, very successfully lowers the LDL cholesterolplasma concentration, resulting in a significant reduction of themortality of patients at risk; however, convincing treatment strategiesfor the therapy of patients having an unfavourable HDL/LDL cholesterolratio and/or hypertriglyeridaemia are still not available to date.

Currently, fibrates are the only therapy option for patients of theserisk groups. They act as weak agonists of theperoxisome-proliferator-activated receptor (PPAR)-alpha (Nature 1990,347, 645-50). A disadvantage of fibrates which have hitherto beenapproved is that their interaction with the receptor is only weak,requiring high daily doses and causing considerable side-effects.

For the peroxisome-proliferator-activated receptor (PPAR)-delta (Mol.Endocrinol. 1992, 6, 1634-41), first pharmacological findings in animalmodels indicate that potent PPAR-delta-agonists may likewise lead to animprovement in the HDL/LDL cholesterol ratio and inhypertriglyceridaemia.

WO 00/23407 discloses PPAR modulators for treating obesity,atherosclerosis and/or diabetes. WO 93/15051 and EP 636 608-A1 describe1-benzenesulphonyl-1,3-dihydroindol-2-one derivatives as vasopressinand/or oxytocin antagonists for the treatment of various disorders.

It was an object of the present invention to provide novel compoundssuitable for use as PPAR-delta modulators.

It has now been found that compounds of the general formula (I)

in which

-   -   A represents the group C—R¹¹ or represents N,        -   where        -   R¹¹ represents hydrogen or (C₁-C₄)-alkyl,    -   X represents O, S or CH₂,    -   R₁ represents (C₆-C₁₀)-aryl or represents 5- to 10-membered        heteroaryl having up to three heteroatoms from the group        consisting of N, O and S, which radicals may for their part each        be mono- to trisubstituted by identical or different        substituents selected from the group consisting of halogen,        cyano, nitro, (C₁-C₆)-alkyl (which for its part may be        substituted by hydroxyl), (C₁-C₆)-alkoxy, phenoxy, benzyloxy,        trifluoromethyl, trifluoromethoxy, (C₂-C₆)-alkenyl, phenyl,        benzyl, (C₁-C₆)-alkylthio, (C₁-C₆)-alkylsulphonyl,        (C₁-C₆)-alkanoyl, (C₁-C₆)-alkoxycarbonyl, carboxyl, amino,        (C₁-C₆)-acylamino, mono- and di-(C₁-C₆)-alkylamino and 5- or        6-membered heterocyclyl having up to two heteroatoms from the        group consisting of N, O and S,        -   or represents a group of the formula    -   R² and R³ are identical or different and independently of one        another represent hydrogen or (C₁-C₆)-alkyl or together with the        carbon atom to which they are attached form a 3- to 7-membered        spiro-linked cycloalkyl ring,    -   R⁴ represents hydrogen or (C₁-C₆)-alkyl,    -   R⁵ represents hydrogen or (C₁-C₆)-alkyl,    -   R⁶ represents hydrogen or (C₁-C₆)-alkyl,    -   R⁷ represents hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or        halogen,    -   R⁸ and R⁹ are identical or different and independently of one        another represent hydrogen or (C₁-C₄)-alkyl, and    -   R¹⁰ represents hydrogen or represents a hydrolysable group which        can be degraded to the corresponding carboxylic acid,    -   and their pharmaceutically acceptable salts, solvates and        solvates of the salts,    -   have pharmacological action and can be used as medicaments or        for preparing medicament formulations.

In the context of the invention, in the definition of R¹⁰, ahydrolysable group means a group which, in particular in the body,causes the —C(O)OR¹⁰ grouping to be converted into the correspondingcarboxylic acid (R¹⁰=hydrogen). Such groups are, by way of example andby way of preference: benzyl, (C₁-C₆)-alkyl or (C₃-C₈)-cycloalkyl whichare in each case optionally mono- or polysubstituted by identical ordifferent substituents from the group consisting of halogen, hydroxyl,amino, (C₁-C₆)-alkoxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkoxycarbonylamino or (C₁-C₆)-alkanoyloxy, or in particular(C₁-C₄)-alkyl which is optionally mono- or polysubstituted by identicalor different substituents from the group consisting of halogen,hydroxyl, amino, (C₁-C₄)-alkoxy, carboxyl, (C₁-C₄)-alkoxycarbonyl,(C₁-C₄)-alkoxycarbonylamino or (C₁-C₄)-alkanoyloxy.

In the context of the invention, (C₁-C₆)-alkyl and (C₁-C₄)-alkylrepresent a straight-chain or branched alkyl radical having 1 to 6 and 1to 4 carbon atoms, respectively. Preference is given to a straight-chainor branched alkyl radical having 1 to 4 carbon atoms. The followingradicals may be mentioned by way of example and by way of preference:methyl, ethyl, n-propyl, isopropyl and t-butyl.

In the context of the invention, (C₂-C₆)-alkenyl represents astraight-chain or branched alkenyl radical having 2 to 6 carbon atoms.Preference is given to a straight-chain or branched alkenyl radicalhaving 2 to 4 carbon atoms. The following radicals may be mentioned byway of example and by way of preference: vinyl, allyl, isopropenyl andn-but-2-en-1-yl.

In the context of the invention, (C₃-C₈)-cycloalkyl represents amonocyclic cycloalkyl group having 3 to 8 carbon atoms. The followingradicals may be mentioned by way of example and by way of preference:cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the context of the invention, (C₆-C₁₀)-aryl represents an aromaticradical having preferably 6 to 10 carbon atoms. Preferred aryl radicalsare phenyl and naphthyl.

In the context of the invention, (C₁-C₆)-alkoxy and (C₁-C₄)-alkoxyrepresent a straight-chain or branched alkoxy radical having 1 to 6 and1 to 4 carbon atoms, respectively. Preference is given to astraight-chain or branched alkoxy radical having 1 to 4 carbon atoms.The following radicals may be mentioned by way of example and by way ofpreference: methoxy, ethoxy, n-propoxy, isopropoxy and t-butoxy.

In the context of the invention, (C₁-C₆)-alkoxycarbonyl and(C₁-C₄)-alkoxycarbonyl represent a straight-chain or branched alkoxyradical having 1 to 6 and 1 to 4 carbon atoms, respectively, whichradical is attached via a carbonyl group. Preference is given to astraight-chain or branched alkoxycarbonyl radical having 1 to 4 carbonatoms. The following radicals may be mentioned by way of example and byway of preference: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl and t-butoxycarbonyl.

In the context of the invention, (C₁-C₆)-alkoxycarbonylamino and(C₁-C₄)-alkoxycarbonylamino represent an amino group having astraight-chain or branched alkoxycarbonyl substituent which has 1 to 6and 1 to 4 carbon atoms, respectively, in the alkoxy radical and whichis attached via the carbonyl group. Preference is given to analkoxycarbonylamino radical having 1 to 4 carbon atoms. The followingradicals may be mentioned by way of example and by way of preference:methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino andt-butoxycarbonylamino.

In the context of the invention, (C₁-C₆)-alkanoyl represents astraight-chain or branched alkyl radical having 1 to 6 carbon atomswhich carries a doubly attached oxygen atom in the 1-position and isattached via the 1-position. Preference is given to a straight-chain orbranched alkanoyl radical having 1 to 4 carbon atoms. The followingradicals may be mentioned by way of example and by way of preference:formyl, acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl andn-hexanoyl.

In the context of the invention, (C₁-C₆)-alkanoyloxy and(C₁-C₄)-alkanoyloxy represent a straight-chain or branched alkyl radicalhaving 1 to 6 and 1 to 4 carbon atoms, respectively, which carries adoubly attached oxygen atom in the 1-position and is attached in the1-position via a further oxygen atom. Preference is given to analkanoyloxy radical having 1 to 4 carbon atoms. The following radicalsmay be mentioned by way of example and by way of preference: acetoxy,propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy, n-hexanoyloxy.

In the context of the invention, mono-(C₁-C₆)-alkylamino andmono-(C₁-C₄)-alkylamino represent an amino group having a straight-chainor branched alkyl substituent of 1 to 6 and 1 to 4 carbon atoms,respectively. Preference is given to a straight-chain or branchedmonoalkylamino radical having 1 to 4 carbon atoms. The followingradicals may be mentioned by way of example and by way of preference:methylamino, ethylamino, n-propylamino, isopropylamino and t-butylamino.

In the context of the invention, di-(C₁-C₆)-alkylamino anddi-(C₁-C₄)-alkylamino represent an amino group having two identical ordifferent straight-chain or branched alkyl substituents having in eachcase 1 to 6 and 1 to 4 carbon atoms, respectively. Preference is givento straight-chain or branched dialkylamino radicals having in each case1 to 4 carbon atoms. The following radicals may be mentioned by way ofexample and by way of preference: N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino,N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.

In the context of the invention, (C₁-C₆)-acylamino represents an aminogroup having a straight-chain or branched alkanoyl substituent which has1 to 6 carbon atoms and is attached via the carbonyl group. Preferenceis given to an acylamino radical having 1 or 2 carbon atoms. Thefollowing radicals may be mentioned by way of example and by way ofpreference: formamido, acetamido, propionamido, n-butyramido andpivaloylamido.

In the context of the invention, (C₁-C₆)-alkylthio represents astraight-chain or branched alkylthio radical having 1 to 6 carbon atoms.Preference is given to a straight-chain or branched alkylthio radicalhaving 1 to 4 carbon atoms. The following radicals may be mentioned byway of example and by way of preference: methylthio, ethylthio,n-propylthio, isopropylthio, t-butylthio, n-pentylthio and n-hexylthio.

In the context of the invention, (C₁-C₆)-alkylsulphonyl represents astraight-chain or branched alkylsulphonyl radical having 1 to 6 carbonatoms. Preference is given to a straight-chain or branchedalkylsulphonyl radical having 1 to 4 carbon atoms. The followingradicals may be mentioned by way of example and by way of preference:methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl,t-butylsulphonyl, n-pentylsulphonyl and n-hexylsulphonyl.

In the context of the invention, 5- to 10-membered and 5- or 6-memberedheteroaryl having up to 3 or up to 2 identical or different heteroatoms,respectively, from the group consisting of N, O and S represents a mono-or optionally bicyclic aromatic heterocycle (heteroaromatic) which isattached via a ring carbon atom or, if appropriate, via a ring nitrogenatom of the heteroaromatic. Examples which may be mentioned are:furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, indolyl,indazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl,quinoxalinyl. Preference is given to 5- or 6-membered heteroarylradicals having up to two nitrogen atoms, such as, for example,imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl.

In the context of the invention, 5- or 6-membered heterocyclyl having upto 2 heteroatoms from the group consisting of N, O and S represents asaturated heterocycle which is attached via a ring carbon atom or, ifappropriate, via a ring nitrogen atom of the heterocycle. The followingradicals may be mentioned by way of example and by way of preference:tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl andthiomorpholinyl.

In the context of the invention, halogen includes fluorine, chlorine,bromine and iodine. Preference is given to chlorine or fluorine.

Depending on the substitution pattern, the compounds according to theinvention can exist in stereoisomeric forms which are either like imageand mirror image (enantiomers) or not like image and mirror image(diastereomers). The invention relates both to the enantiomers ordiastereomers and to their respective mixtures. The racemic forms, likethe diastereomers, can be separated in a known manner into thestereoisomerically uniform components.

Furthermore, certain compounds can be present in tautomeric forms. Thisis known to the person skilled in the art, and such compounds arelikewise included in the scope of the invention.

The compounds according to the invention can also be present as salts.In the context of the invention, preference is given to physiologicallyacceptable salts.

Physiologically acceptable salts can be salts of the compounds accordingto the invention with inorganic or organic acids. Preference is given tosalts with inorganic acids such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid or sulphuric acid, or to salts withorganic carboxylic or sulphonic acids such as, for example, acetic acid,propionic acid, maleic acid, fumaric acid, malic acid, citric acid,tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid,ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid ornaphthalenedisulphonic acid.

Physiologically acceptable salts can also be salts of the compoundsaccording to the invention with bases, such as, for example, metal orammonium salts. Preferred examples are alkali metal salts (for examplesodium salts or potassium salts), alkaline earth metal salts (forexample magnesium salts or calcium salts), and also ammonium salts whichare derived from ammonia or organic amines, such as, for example,ethylamine, di- or triethylamine, ethyldiisopropylamine,monoethanolamine, di- or triethanolamine, dicyclohexylamine,dimethylaminoethanol, dibenzylamine, N-methylmorpholine,dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine,ethylenediamine or 2-phenylethylamine.

The compounds according to the invention can also be present in the formof their solvates, in particular in the form of their hydrates.

Preference is given to compounds of the general formula (I) in which

-   -   A represents the group C—R¹¹ or represents N,        -   where        -   R¹¹ represents hydrogen or methyl,    -   X represents O or S,    -   R¹ represents phenyl or represents 5- or 6-membered heteroaryl        having up to two heteroatoms from the group consisting of N, O        and S, which radicals may for their part each be mono- or        disubstituted by identical or different substituents selected        from the group consisting of fluorine, chlorine, cyano,        (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, phenoxy, benzyloxy,        trifluoromethyl, trifluoromethoxy, vinyl, phenyl, benzyl,        methylthio, methylsulphonyl, acetyl, propionyl,        (C₁-C₄)-alkoxycarbonyl, amino, acetylamino, mono- and        di-(C₁-C₄)-alkylamino,    -   R² and R³ are identical or different and independently of one        another represent hydrogen or (C₁-C₄)-alkyl or together with the        carbon atom to which they are attached form a 5- or 6-membered        spiro-linked cycloalkyl ring,    -   R⁴ represents hydrogen or methyl,    -   R⁵ represents hydrogen, methyl or ethyl,    -   R⁶ represents hydrogen or methyl,    -   R⁷ represents hydrogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, fluorine        or chlorine,    -   R⁸ and R⁹ are identical or different and independently of one        another represent hydrogen or methyl, and    -   R¹⁰ represents hydrogen.

Particular preference is given to compounds of the general formula (I)in which

-   -   A represents CH or N,    -   X represents O,    -   R¹ represents phenyl or represents pyridyl which for their part        may each be mono- or disubstituted by identical or different        substituents selected from the group consisting of fluorine,        chlorine, methyl, tert-butyl, methoxy, trifluoromethyl,        trifluoromethoxy, methylthio, amino and dimethylamino,    -   R² represents hydrogen or methyl,    -   R³ represents methyl, isopropyl or tert-butyl, or    -   R² and R³ together with the carbon atom to which they are        attached form a spiro-linked cyclohexane ring,    -   R⁴ represents hydrogen or methyl,    -   R⁵ represents hydrogen, methyl or ethyl,    -   R⁶ represents hydrogen or methyl,    -   R⁷ represents methyl,    -   R⁸ and R⁹ each represent hydrogen, and    -   R¹⁰ represents hydrogen.

The general or preferred radical definitions listed above apply both tothe end products of the formula (I) and, correspondingly, to thestarting materials and intermediates required in each case for thepreparation.

The individual radical definitions given in the respective combinationsor preferred combinations of radicals are, independently of therespectively given combinations of radicals, also replaced by anyradical definitions of other combinations.

Of particular importance are compounds of the formula (I-A)

in which

-   -   R² represents hydrogen,    -   R³ represents methyl, isopropyl or tert-butyl, or    -   R² and R³ both represent methyl or together with the carbon atom        to which they are attached form a spiro-linked cyclohexane ring,        and    -   A, R¹, R⁴, R⁵ and R⁶ are each as defined above.

Moreover, we have found a process for preparing the compounds of thegeneral formula (I) according to the invention, which process ischaracterized in that

compounds of the general formula (II)

in which A, R², R³, R⁴ and R⁵ are each as defined above and

Y represents chlorine or bromine,

are initially converted using a compound of the general formula (III)

in which X, R⁶, R⁷, R⁸ and R⁹ are each as defined above and

T represents benzyl or (C₁-C₆)-alkyl,

in an inert solvent in the presence of a base into compounds of thegeneral formula (IV)

in which A, T, X, Y, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each asdefined above,

these compounds are then reacted in a coupling reaction with a compoundof the general formula (V)

-   -   in which R¹ is as defined above and    -   R¹² represents hydrogen or methyl or both radicals together form        a —CH₂CH₂— or —C(CH₃)₂—C(CH₃)₂— bridge,    -   in an inert solvent in the presence of a suitable palladium        catalyst and a base to give compounds of the general formula        (I-B)

in which A, T, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each asdefined above,

[cf., for example, W. Hahnfeld, M. Jung, Pharmazie 1994, 49, 18-20;idem, Liebigs Ann. Chem. 1994, 59-64],

the compounds (I-B) are then reacted with acids or bases or, if Trepresents benzyl, also hydrogenolytically, to give the correspondingcarboxylic acids of the general formula (I-C)

in which A, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each as definedabove,

and the carboxylic acids (I-C) are, if appropriate, further modified byknown esterification methods to give compounds of the general formula(I).

In the reaction sequence described above, the step of the couplingreaction [cf. (TV)+(V)→(I-B)] and the ester cleavage [cf. (I-B)→(I-C)]can optionally also be carried out in reverse order; in the couplingreaction, it is also possible to carry out a basic ester cleavage insitu.

Inert solvents for process step (II)+(III)→(IV) are, for example,halogenated hydrocarbons, such as dichloromethane, trichloromethane,carbon tetrachloride, trichloroethane, tetrachloroethane,1,2-dichloroethane or trichloroethylene, ethers, such as diethyl ether,dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycoldimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane,cyclohexane or mineral oil fractions, or other solvents, such asnitromethane, ethyl acetate, acetone, dimethylformamide, dimethylsulphoxide, acetonitrile, N-methylpyrrolidinone or pyridine. It is alsopossible to use mixtures of the solvents mentioned. Preference is givento dichloromethane or tetrahydrofuran.

Suitable bases for process step (II)+(E)→(IV) are the customaryinorganic or organic bases. These preferably include alkali metalhydroxides such as, for example, lithium hydroxide, sodium hydroxide orpotassium hydroxide, alkali metal or alkaline earth metal carbonates,such as sodium carbonate, potassium carbonate or calcium carbonate,alkali metal hydrides, such as sodium hydride, or organic amines, suchas pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine orN-methylpiperidine. Particular preference is given to amine bases suchas triethylamine, pyridine or ethyldiisopropylamine, if appropriate inthe presence of catalytic amounts (about 10 mol %) of4-N,N-dimethylaminopyridine or 4-pyrrolidinopyridine.

Here, the base is employed in an amount of from 1 to 5, preferably 1 to2.5, mol per mole of the compound of the general formula (III).

The reaction is generally carried out in a temperature range of from−20° C. to +100° C., preferably from 0° C. to +75° C. The reaction canbe carried out at atmospheric, elevated or reduced pressure (for examplefrom 0.5 to 5 bar). In general, the reaction is carried out atatmospheric pressure.

Inert solvents for process step (IV)+(V)→(I-B) are, for example, ethers,such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl etheror diethylene glycol dimethyl ether, alcohols, such as methanol,ethanol, n-propanol, isopropanol, n-butanol or tert-butanol,hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane ormineral oil fractions, or other solvents, such as dimethylformamide,acetonitrile or else water. It is also possible to use mixtures of thesolvents mentioned. Preference is given to toluene, dimethylformamide oracetonitrile.

Suitable bases for process step (IV)+(V)→(I-B) are the customaryinorganic or organic bases. These preferably include alkali metalhydroxides, such as, for example, lithium hydroxide, sodium hydroxide orpotassium hydroxide, alkali metal or alkaline earth metal carbonates,such as sodium carbonate, potassium carbonate or calcium carbonate,alkali metal phosphates, such as sodium phosphate or potassiumphosphate, or organic amines, such as pyridine, triethylamine,ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine.Particular preference is given to sodium carbonate or potassiumcarbonate or potassium phosphate.

Here, the base is employed in an amount of from 1 to 5, preferably from2 to 3, mol per mole of the compound of the general formula (IV).

Suitable palladium catalysts for process step (IV)+(V)→(I-B) are,preferably, palladium(0) or palladium(II) compounds which are used inpreformed form, such as, for example,[1,1′-bis(diphenylphosphino)ferrocenyl]palladium(II) chloride orbis(triphenylphosphine)palladium(II) chloride, or which may be generatedin situ from a suitable palladium source, such as, for example,bis(dibenzylideneacetone)palladium(0) ortetrakis(triphenylphosphine)palladium(0), and a suitable phosphineligand.

The reaction is generally carried out in a temperature range of from 0°C. to +150° C., preferably from +20° C. to +100° C. The reaction can becarried out at atmospheric, elevated or reduced pressure (for examplefrom 0.5 to 5 bar). In general, the reaction is carried out atatmospheric pressure.

Inert solvents for process step (I-B)→(I-C) are, for example,halogenated hydrocarbons, such as dichloromethane, 1,2-dichloroethane ortrichloroethylene, ethers, such as diethyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethylether, alcohols, such as methanol, ethanol, n-propanol, isopropanol,n-butanol or tert-butanol, hydrocarbons, such as benzene, xylene,toluene, hexane, cyclohexane or mineral oil fractions, or othersolvents, such as nitromethane, acetone, dimethylformamide, dimethylsulphoxide, acetonitrile or N-methylpyrrolidinone. It is also possibleto use mixtures of the solvents mentioned. Preference is given toalcohols such as methanol or ethanol.

Suitable bases for process step (I-B)→(I-C) are the customary inorganicbases. These preferably include alkali metal hydroxides, such as, forexample, lithium hydroxide, sodium hydroxide or potassium hydroxide, oralkali metal or alkaline earth metal carbonates, such as sodiumcarbonate, potassium carbonate or calcium carbonate. Particularpreference is given to lithium hydroxide or sodium hydroxide.

Here, the base is employed in an amount of from 1 to 5, preferably from1 to 3, mol per mole of the compound of the general formula (I-B).

Suitable acids for process step (I-B)→(I-C) are the customary inorganicacids, such as, for example, hydrochloric acid or sulphuric acid, orsulphonic acids, such as toluenesulphonic acid, methanesulphonic acid ortrifluoromethanesulphonic acid, or carboxylic acids, such astrifluoroacetic acid.

In general, the reaction is carried out in a temperature range of from−20° C. to +100° C., preferably from 0° C. to +30° C. The reaction canbe carried out at atmospheric, elevated or reduced pressure (for examplefrom 0.5 to 5 bar). In general, the reaction is carried out atatmospheric pressure.

The compounds of the general formula (II) are known or can be preparedanalogously to processes known from the literature by initiallyconverting compounds of the general formula (VI)

in which A, Y and R⁵ are each as defined above,

with sodium nitrite and tin(II) chloride in the presence of an acid intohydrazine derivatives of the general formula (VII)

in which A, Y and R⁵ are each as defined above,

then reacting these in the presence of an acid or Lewis acid, ifappropriate in an inert solvent, with a compound of the general formula(VIII)

in which R², R³ and R⁴ are each as defined above,

if R² and R³ in (VIII) are both not hydrogen, to compounds of thegeneral formula (IX), or, if R³ in (VIII) represents hydrogen, tocompounds of the general formula (X)

in which A, Y, R⁴ and R⁵ are each as defined above,

and then reducing the compounds (IX) or (X) with the aid of aborohydride, aluminium hydride or silicon hydride, such as, for example,sodium borohydride or sodium cyanoborohydride, or by hydrogenation inthe presence of a suitable catalyst, such as, for example, Raney nickel[for process steps (VII)+(VIII)→(IX)→(II) cf., for example, P. E.Maligres, I. Houpis, K. Rossen, A. Molina, J. Sager, V. Upadhyay, K. M.Wells, R. A. Reamer, J. E. Lynch, D. Askin, R. P. Volante, P. J. Reider,Tetrahedron 1997, 53, 10983-10992].

Inert solvents for process step (VI)→(VII) are, for example, ethers,such as dioxane, glycol dimethyl ether or diethylene glycol dimethylether, alcohols, such as methanol, ethanol, n-propanol, iso-propanol,n-butanol or tert-butanol, or other solvents, such as dimethylformamide,dimethyl sulphoxide, N-methylpyrrolidinone or water. It is also possibleto use mixtures of the solvents mentioned. The preferred solvent iswater.

Suitable acids for process step (VI)→(VII) are the customary inorganicor organic acids. These preferably include hydrochloric acid, sulphuricacid or phosphoric acid, or carboxylic acids, such as formic acid,acetic acid or trifluoroacetic acid, or sulphonic acids, such astoluenesulphonic acid, methanesulphonic acid ortrifluoromethanesulphonic acid. Particular preference is given tosemiconcentrated to concentrated aqueous hydrochloric acid whichsimultaneously acts as solvent.

The reaction is generally carried out in a temperature range of from−30° C. to +80° C., preferably from −10° C. to +25° C. The reaction canbe carried out at atmospheric, elevated or reduced pressure (for examplefrom 0.5 to 5 bar). In general, the reaction is carried out atatmospheric pressure.

Inert solvents for process step (VII)+(VIII)→(IX) or (X) are, forexample, halogenated hydrocarbons, such as dichloromethane,trichloromethane, carbon tetrachloride, trichloroethane,tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers, suchas dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycoldimethyl ether, alcohols, such as methanol, ethanol, n-propanol,isopropanol, n-butanol or tert-butanol, or hydrocarbons, such asbenzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions,or other solvents, such as acetonitrile or water. It is also possible touse mixtures of the solvents mentioned. It is also possible to carry outthe reaction without any solvent. If R³ represents hydrogen and Arepresents CH or N, the reaction is preferably carried out without anysolvent to give the product (X); if R² and R³ are both not hydrogen andA represents CH, the reaction is preferably carried out in a mixture oftoluene and acetonitrile to give the product (IX).

Suitable acids for process step (VII)+(VIII)→(IX) or (X) are thecustomary inorganic or organic acids. These preferably includehydrochloric acid, sulphuric acid or phosphoric acid, or carboxylicacids, such as formic acid, acetic acid or trifluoroacetic acid, orsulphonic acids, such as toluenesulphonic acid, methanesulphonic acid ortrifluoromethanesulphonic acid. Alternatively, the customary Lewisacids, such as, for example, boron trifluoride, aluminium trichloride orzinc chloride are also suitable. Here, the acid is employed in an amountof from 1 to 10 mol per mole of the compound of the general formula(VII). If R³ represents hydrogen and A represents CH or N, the reactionis preferably carried out using 1 to 2 mol of zinc chloride to give theproduct (X), and if R² and R³ are both not hydrogen and A represents CH,the reaction is preferably carried out using 2 to 5 mol oftrifluoroacetic acid to give the product (IX).

The reaction is generally carried out in a temperature range of from 0°C. to +250° C. If R³ represents hydrogen and A represents CH or N, thereaction is preferably carried out in a temperature range of from +130°C. to +200° C. to give the product (X); if R² and R³ are both nothydrogen and A represents CH, the reaction is preferably carried out ina temperature range of from 0° C. to +50° C. to give the product (IX).The reaction can be carried out at atmospheric, elevated or reducedpressure (for example from 0.5 to 5 bar). In general, the reaction iscarried out at atmospheric pressure.

Reducing agents suitable for process step (IX) or (X)→(II) areborohydrides, aluminium hydrides or silicon hydrides, such as, forexample, borane, diborane, sodium borohydride, sodium cyanoborohydride,lithium aluminium hydride or triethylsilane, if appropriate in thepresence of an acid or Lewis acid, such as, for example, acetic acid,trifluoroacetic acid, aluminium trichloride or boron trifluoride, orhydrogenation with hydrogen in the presence of a suitable catalyst, suchas, for example, palladium on activated carbon, platinum oxide or Raneynickel. In the case of compounds of the general formula (X) in which Arepresents N, preference is given to hydrogenation using Raney nickel ascatalyst, and if A in (X) represents CH, preference is given toreduction with sodium cyanoborohydride. In the case of compounds of thegeneral formula (IX), preference is given to using sodium borohydride.

Suitable solvents for process step (IX) or (X)→(II) are, for example,ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethylether or diethylene glycol dimethyl ether, alcohols, such as methanol,ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, orhydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane ormineral oil fractions, or other solvents, such as acetonitrile, aceticacid or water. It is also possible to use mixtures of the solventsmentioned. For the hydrogenation of the compounds of the general formula(X) in which A represents N, preference is given to using ethanol, andfor the reduction in the case where A in (X) represents CH, preferenceis given to using acetic acid, a large excess of which is added as acidto the reducing agent and simultaneously serves as solvent. For thereduction of the compounds of the general formula (IX), preference isgiven to using a mixture of methanol and toluene/acetonitrile [from thereaction (VII)→(IX), with addition of 2 to 5 mol of trifluoroaceticacid] in a ratio of from 1:1 to 1:10.

The reaction is generally carried out in a temperature range of from−20° C. to +200° C. Here, the hydrogenation of the compounds (X) inwhich A represents N is preferably carried out in a temperature range offrom +150° C. to +200° C., whereas the reduction of the compounds (IX)and (X) in which A represents CH is preferably carried out in atemperature range of from −10° C. to +50° C. The reaction can be carriedout at atmospheric, elevated or reduced pressure (for example from 0.5to 150 bar). Whereas the hydrogenation of the compounds (X) in which Arepresents N is preferably carried out in a pressure range of from 50 to150 bar of hydrogen, the reduction of the compounds (IX) or (X) in whichA represents CH is generally carried out at atmospheric pressure.

The compounds of the general formula (III) are known or can be preparedanalogously to processes known from the literature, for example byinitially converting a compound of the general formula (XI)

in which R⁶, R⁷ and X are each as defined above,

with a compound of the general formula (XII)

in which R⁸, R⁹ and T are each as defined above,

in an inert solvent in the presence of a base into a compound of thegeneral formula (XIII)

in which R⁶, R⁷, R⁸, R⁹, X and T are each as defined above,

and then reacting this compound with chlorosulphonic acid [cf., forexample, P. D. Edwards, R. C. Mauger, K. M. Cottrell, F. X. Morris, K.K. Pine, M. A. Sylvester, C. W. Scott, S. T. Furlong, Bioorg. Med. Chem.Lett. 2000, 10, 2291-2294].

Inert solvents for process step (XI)+(XII)→(XIII) are, for example,ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethylether or diethylene glycol dimethyl ether, hydrocarbons, such asbenzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions,or other solvents, such as acetone, dimethylformamide, dimethylsulphoxide, acetonitrile or N-methylpyrrolidinone. It is also possibleto use mixtures of the solvents mentioned. Preference is given todimethylformamide or acetone.

Suitable bases for process step (XI)+(XII)→(XIII) are the customaryinorganic or organic bases. These preferably include alkali metalhydroxides, such as, for example, lithium hydroxide, sodium hydroxide orpotassium hydroxide, alkali metal or alkaline earth metal carbonates,such as sodium carbonate, potassium carbonate or calcium carbonate,alkali metal hydrides, such as sodium hydride, or organic amines, suchas pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine orN-methylpiperidine. Particular preference is given to potassiumcarbonate.

Here, the base is employed in an amount of from 1 to 5, preferably from1 to 2, mol per mole of the compound of the general formula (XI).

The reaction is generally carried out in a tempereature range of from−20° C. to +150° C., preferably from 0° C. to +80° C. The reaction canbe carried out at atmospheric, elevated or reduced pressure (for examplefrom 0.5 to 5 bar). In general, the reaction is carried out atatmospheric pressure.

The compounds of the general formulae (V), (VI), (VIII), (XI) and (XII)are commercially available, known from the literature or can be preparedanalogously to processes known from the literature.

The process according to the invention can be illustrated by reactionsscheme 1 and 2 below:

a) NaNO₂, SnCl₂, HCl; b) CH₃CH₂OH, RT; c) ZnCl₂, 170° C., 30 min; d)NaCNBH₃, CH₃COOH, 35° C., 16 h; for A=N: Raney nickel, 180° C., 80 barH₂, e) DMAP, TEA, CH₂Cl₂, RT; f) Pd(PPh₃)₂Cl, DMF, aq. Na₂CO₃, 100° C.,15 h.

a) NaNO₂, SnCl₂, HCl; b) TFA, 35° C.; c) NaBH₄, CH₃OH, −10° C.; d) THF,TEA, −5° C.; e) KOH, THF/H₂O, RT; f) Pd catalyst, DME, Na₂CO₃, 60° C.,14 h [literature for reaction steps b, c): P. E. Maligres, I. Houpis, K.Rossen, A. Molina, J. Sager, V. Upadhyay, K. M. Wells, R. A. Reamer, J.E. Lynch, D. Askin, R. P. Volante, P. J. Reider, Tetrahedron 1997, 53,10983-10992].

The compounds of the formula (I) according to the invention have asurprising and useful spectrum of pharmacological activity and cantherefore be used as versatile medicaments, in particular for treatingdisorders in which the PPAR delta inhibitor is activiated. Inparticular, they are suitable for treating coronary heart disease, forthe prophylaxis of myocardial infarction and for the treatment ofrestenosis after coronary angioplasty or stenting. The compounds of theformula (I) according to the invention are preferably suitable fortreating stroke, CNS disorders, Alzheimer's, osteoporosis,arteriosclerosis and hypercholesterolaemia, for increasingpathologically low HDL levels and for lowering elevated triglyceride andLDL levels. In addition, they can be used for treating obesity,diabetes, for treating metabolic syndrome (glucose intolerance,hyperinsulinaemia, dyslipidaemia and high blood pressure owing toinsulin resistance), hepatic fibrosis and cancer.

The novel active compounds can be administered alone or, if required, incombination with other active compounds, preferably from the group ofthe CETP inhibitors, antidiabetics, antioxidants, cytostatics, calciumantagonists, antihypertensives, thyroid hormones and/or thyroidmimetics, inhibitors of HMG-CoA reductase, inhibitors of HMG-CoAreductase expression, squalene synthesis inhibitors, ACAT inhibitors,perfusion promoters, platelet aggregation inhibitors, anticoagulants,angiotensin II receptor antagonists, cholesterol absorption inhibitors,MTP inhibitors, aldolase reductase inhibitors, fibrates, niacin,anorectics, lipase inhibitors and PPAR-α and/or PPAR-γ agonists. Furthercombinations with anti-inflammatory agents, for example COX-2inhibitors, NEP inhibitors, ECE inhibitors, vasopeptidase inhibitors,aldose reduction inhibitors, antioxidants, cytostatics, perfusionpromoters and anorectics are possible.

The compounds according to the invention are in each case preferablycombined with an antidiabetic or a plurality of antidiabetics mentionedin the Rote Liste 2002/II, Chapter 12,

-   -   with one or more antithrombotics, by way of example and by way        of preference from the group of the platelet aggregation        inhibitors or the anticoagulants,    -   with one or more antihypertensives, by way of example and by way        of preference from the group of the calcium antagonists,        angiotensin AII antagonists, ACE inhibitors, beta blockers and        the diuretics and/or    -   with one or more lipid metabolism-modifying active compounds        from the group of the thyroid receptor agonists, cholesterol        synthesis inhibitors such as, by way of example and by way of        preference, HMG-CoA reductase or squalene synthesis inhibitors,        ACAT inhibitors, MPT inhibitors, PPAR agonists, fibrates,        cholesterol absorption inhibitors, lipase inhibitors, polymeric        bile acid absorbers, lipoprotein(a) antagonists.

Antidiabetics are to be understood as meaning, by way of example or byway of preference, insulin and insulin derivatives, and also orallyactive hypoglycaemics.

Here, insulin and insulin derivatives include both insulins of animal,human or biotechnological origin, and also mixtures thereof.

The orally active hypoglycaemics include, by way of example and by wayof preference, sulphonyl ureas, biguadines, meglitinide derivatives,oxoadiazolidinones, thiazolindinediones, glucosidase inhibitors,glucagon antagonists, GLP-1 agonists, insulin sensitizers, inhibitors ofliver enzymes involved in the stimulation of gluconeogenesis and/orglycogenolysis, modulators of glucose uptake and potassium channelopeners, for example those disclosed in WO 97/26265 and WO 99/03861 byNovo Nordisk A/S.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with insulin.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a sulphonyl urea, such as, by way ofexample and by way of preference, tolbutamide, glibenclanide,glimepiride, glipizide or gliclazide.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a biguanide, such as, by way of exampleand by way of preference, metformine.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a meglitinde derivative, such as, byway of example and by way of preference, repaglinide or nateglinide.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a PPAR gamma agonist, for example fromthe class of thiazolidinediones, such as, by way of example and by wayof preference, pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a mixed PPAR alpha/gamma agonist, suchas, by way of example and by way of preference, GI-262570 (farglitazar),GW 2331, GW 409544, AVE 8042, AVE 8134, AVE 0847, MK-0767 (KRP-297),AZ-242.

Antithrombotics are to be understood as meaning, by way of preference,compounds from the group of the platelet aggregation inhibitors, suchas, by way of example and by way of preference, aspirin, clopidogrel,ticlopidine, dipyridamole, or of the anticoagulants.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a thrombin inhibitor, such as, by wayof example and by way of preference, ximelagatran, melagatran,bivalirudin, clexane.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a GPIIb-IIIa antagonist, such as, byway of example and by way of preference, tirofiban, abciximab.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a factor Xa inhibitor, such as, by wayof example and by way of preference, DX 9065a, DPC 906, JTV 803.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with heparin or low molecular weight heparinderivatives.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a vitamin K antagonist, such as, by wayof example and by way of preference, coumarin.

Antihypertensives are to be understood as meaning, by way of example andby way of preference, compounds from the group of the calciumantagonists, such as, by way of example and by way of preference, thecompounds nipfedipine, verapamil, dilitazem, angiotensin, AIIantagonists, ACE inhibitors, beta blockers, and also the diuretics.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with an antagonist of alpha 1 receptors.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with reserpine, minoxidil, diazoxide,dihydralazine, hydralazine, and also nitric oxide-releasing compounds,such as, by way of example and by way of preference, glycerol nitrate ornitroprusside sodium.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with an angiotensin AII antagonist, such as,by way of example and by way of preference, losartan, valsartan,telmisartan.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with an ACE inhibitor, such as, by way ofexample and by way of preference, enalapril, captopril.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a beta blocker, such as, by way ofexample and by way of preference, propranolol, atenolol.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a diuretic, such as, by way of exampleand by way of preference, furosemide.

Lipid metabolism-modifying agents are to be understood as meaning, byway of example and by way of preference, compounds from the group of thethyroid receptor agonists, cholesterols synthesis inhibitors, such asHMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTPinhibitors, PPAR agonists, fibrates, cholesterol absorption inhibitors,lipase inhibitors, polymeric bile acid absorbers, lipoprotein(a)antagonists.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a thyroid receptor agonist, such as, byway of example and by way of preference, D-thyroxine,3,5,3′-triiodothyronine (T3), CGS 23425, axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a squalene synthesis inhibitor, suchas, by way of example and by way of preference, BMS-188494, TAK 457.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with an ACAT inhibitor, such as, by way ofexample and by way of preference, avasimibe.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a cholesterol absorption inhibitor,such as, by way of example and by way of preference, ezetimibe,tiqueside, pamaqueside.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with an MTP inhibitor, such as, by way ofexample and by way of preference, implitapide, BMS-201038, R-103757.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a PPAR alpha agonist, such as, forexample, the fibrates fenobfibrate, clofibrate, bezafibrate,ciprofibrate, gemfibrozil or such as, by way of example and by way ofpreference, GW 9578, GW 7647, LY-518674 or NS-220.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination a CEPT inhibitor, such as, by way of exampleand by way of preference, torcetrapib (CP-5239 414), JJT-705.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a mixed PPAR alpha/gamma agonist, suchas, by way of example and by way of preference, GI-262570 (farglitazar),GW 2331, GW 409544, AVE 8042, AVE 8134, AVE 0847, MK-0767 (KRP-297),AZ-242.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a lipase inhibitor, such as, by way ofexample and by way of preference, orlistat.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a polymeric bile acid adsorber, suchas, by way of example and by way of preference, cholestyramine,colestipol, colesolvam, CholestaGel, colestimide.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with a lipoprotein(a) antagonist, such as,by way of example and by way of preference, gemcabene calcium (CI-1027)or nicotinic acid.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with an antagonist of the niacin receptor.

In a preferred embodiment of the invention, the compounds mentioned areadministered in combination with an LDL receptor inducer.

The invention also provides combinations of the compounds of theformulae (I) to (III) with HMG-CoA reductase inhibitors from the classof the statins, such as, by way of example and by way of preference,lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,rosuvastatin and cerivastatin, pitavastatin.

The activity of the compounds according to the invention can beexamined, for example, in vitro by the transactivation assay describedin the experimental section.

The activity of the compounds according to the invention in vivo can beexamined, for example, by the tests described in the experimentalsection.

Suitable administration forms for administering the compounds of thegeneral formula (I) are all customary administration forms, i.e. oral,parenteral, inhalative, nasal, sublingual, rectal, external, for exampletransdermal, or local, such as, for example, in the case of implants orstents. In the case of parenteral administration, particular mention hasto be made of intravenous, intramuscular and subcutaneousadministration, for example as a subcutaneous depot. Preference is givento oral or parenteral administration. Very particular preference isgiven to oral administration.

Here, the active compounds can be administered on their own or in theform of preparations. Preparations suitable for oral administration are,inter alia, tablets, capsules, pellets, sugar-coated tablets, pills,granules, solid and liquid aerosols, syrups, emulsions, suspensions andsolutions. Here, the active compound has to be present in such an amountthat a therapeutic effect is obtained. In general, the active compoundcan be present in a concentration of from 0.1 to 100% by weight, inparticular from 0.5 to 90% by weight, preferably from 5 to 80% byweight. In particular, the concentration of active compound should be0.5 to 90% by weight, i.e. the active compound should be present inamounts sufficient to reach the dosage range stated.

To this end, the active compounds can be converted in a manner known perse into the customary preparations. This is carried out using inertnon-toxic pharmaceutically acceptable carriers, auxiliaries, solvents,vehicles, emulsifiers and/or dispersants.

Auxiliaries which may be mentioned are, for example: water, non-toxicorganic solvents, such as, for example, paraffins, vegetable oils (forexample sesame oil), alcohols (for example ethanol, glycerol), glycols(for example polyethylene glycol), solid carriers, such as natural orsynthetic ground minerals (for example talc or silicates), sugar (forexample lactose), emulsifiers, dispersants (for examplepolyvinylpyrrolidone) and glidants (for example magnesium sulphate).

In the case of oral administration, tablets may, of course, also containadditives such as sodium citrate, together with additives such asstarch, gelatine and the like. Aqueous preparations for oraladministration may furthermore comprise flavour improvers or colorants.

In the case of oral administration, preference is given to administeringdosages of from 0.001 to 5 mg/kg, preferably from 0.005 to 3 mg/kg, ofbody weight per 24 hours.

The working examples below illustrate the invention. The invention isnot limited to the examples.

LC/MS Methods:

Method A: column: Waters Symmetry C18 50×2.1 mm, 3.5 μm; 0.5 ml/min; A:acetonitrile+0.1% formic acid, B: water+0.1% formic acid; 0 min 10% A, 4min 90% A; 40° C.

Method B: instrument: Finnigan MAT 900S, TSP: P4000, AS3000, UV3000HR;column: Symmetry C 18, 150 mm×2.1 mm, 5.0 μm; mobile phase C: water,mobile phase B: water+0.3 g/l 35% strength hydrochloric acid, mobilephase A: acetonitrile; gradient: 0.0 min 2% A→2.5 min 95% A→5 min 95% A;oven: 70° C.; flow rate: 1.2 ml/min; UV detection: 210 nm.

Method C: instrument: Micromass Quattro LCZ, HP1100; column: SymmetryC18, 50 mm×2.1 mm, 3.5 μm; mobile phase A: acetonitrile+0.1% formicacid, mobile phase B: water+0.1% formic acid; gradient: 0.0 min 10%A→4.0 min 90% A→6.0 min 90% A; oven: 40° C.; flow rate: 0.5 ml/min; UVdetection: 208-400 nm.

Method D: instrument: Micromass Platform LCZ, HP1100; column: SymmetryC18, 50 mm×2.1 mm, 3.5 μm; mobile phase A: acetonitrile+0.1% formicacid, mobile phase B: water+0.1% formic acid; gradient: 0.0 min 10%A→4.0 min 90% A→6.0 min 90% A; oven: 40° C.; flow rate: 0.5 ml/min; UVdetection: 208-400 nm.

Method E: instrument: Micromass Platform LCZ, HP1100; column: SymmetryC18, 50 mm×2.1 mm, 3.5 μm; mobile phase A: acetonitrile+0.5% formicacid, mobile phase B: water+0.5% formic acid; gradient: 0.0 min 90%A→4.0 min 10% A→6.0 min 10% A; oven: 50° C.; flow rate: 0.5 ml/min; UVdetection: 208-400 nm.

Method F: instrument: Micromass TOF-MUX-Interface/Waters600; column:YMC-ODS AQ, 50 mm×2.1 mm, 3.5 μm; temperature: 20° C.; flow rate: 0.8ml/min; mobile phase A: acetonitrile+0.05% formic acid, mobile phase B:water+0.05% formic acid; gradient: 0.0 min 0% A→0.2 min 0% A→2.9 min 70%A→3.1 min 90% A.

GC/MS: Carrier gas: helium Flow rate: 1.5 ml/min Initial temperature:60° C. Temperature gradient: 14° C./min to 300° C., then 1 min const.300° C. Column: HP-5 30 m × 320 μm × 0.25 μm (film thickness) Initialtime: 2 min Front injector temp.: 250° C.

ABBREVIATIONS USED

-   abs. absolute-   aq. aqueous-   DMAP 4-N,N-dimethylaminopyridine-   DME 1,2-dimethoxyethane-   DMF N,N-dimethylformamide-   DMSO dimethyl sulphoxide-   ESI electrospray ionization (MS)-   GC gas chromatography-   LC-MS liquid chromatography-coupled mass spectroscopy-   MS mass spectroscopy-   MW molecular weight-   NMR nuclear magnetic resonance spectroscopy-   R_(f) retention index (TLC)-   RT room temperature-   R_(t) retention time (HPLC)-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran

WORKING EXAMPLES Example 1[4-({3-Isopropyl-7-methyl-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indol-1-yl}-sulphonyl)-2-methylphenoxy]aceticacid

Step a):

1-(4-Bromo-2-methylphenyl)hydrazine

In 190 ml of concentrated hydrochloric acid, 50 g (267.7 mmol) of4-bromo-2-methylaniline are heated at 80° C. for 30 min. After coolingto 5° C., 18.5 g (267.7 mmol) of sodium nitrite in 95 ml of water areadded dropwise over a period of 30 min. After 30 minutes of stirring at5° C., the reaction mixture is added dropwise over a period of 45 min toa solution of 384 g (2 mol) of tin chloride in 190 ml of concentratedhydrochloric acid. After a further 45 min at RT, the suspension is madealkaline using 50% strength aqueous sodium hydroxide solution. Theprecipitate is filtered off and extracted repeatedly withdichloromethane and ethyl acetate. The combined organic phases are driedover magnesium sulphate and concentrated. This gives 43.6 g (81% oftheory) of the product as beige crystals.

LC-MS (method B): R_(t)=2.06 min

MS (ESIpos): m/z=201 (M+H)⁺

Step b):

5-Bromo-3-isopropyl-7-methyl-1H-indole

7 g (34.8 mmol) of 1-(4-bromo-2-methylphenyl)hydrazine are suspended in14 ml of ethanol, and 3.9 g (45 mmol) of isovaleraldehyde are added. Themixture is stirred at RT for 30 minutes and the solvent is then removedunder reduced pressure and the intermediate is, without furtherpurification, melted at 170° C. with 5.2 g (38 mmol) of anhydrous zincchloride. After 30-45 min, the melt is cooled to RT, taken up indichloromethane and extracted with dilute hydrochloric acid and water.The organic phase is dried over magnesium sulphate and the solvent isremoved under reduced pressure. The crude product is dissolved in ethylacetate and purified on silica gel (mobile phase: cyclohexane/ethylacetate 9:1). This gives 4.2 g (48% of theory).

LC-MS (method B): R_(t)=3.15 min

MS (ESIpos): m/z=253 (M+H)⁺

¹H-NMR (300 MHz, acetone-d₆): δ=1.51 (d, 6 H), 2.67 (s, 3H), 3.37 (m,1H), 7.23 (s, 1H), 7.34 (s, 1H), 7.78 (s, 1H), 10.28 (s, 1H).

Step c):

5-Bromo-3-isopropyl-7-methylindoline

4.1 g (16.3 mmol) of 5-bromo-3-isopropyl-7-methyl-1H-indole aredissolved in 30 ml of glacial acetic acid and, at RT, 5.1 g (81 mmol) ofsodium cyanoborohydride are added a little at a time. The reactionmixture is warmed at 35° C. for 16 hours and then hydrolysed with waterand extracted twice with ethyl acetate. The extract is dried over sodiumsulphate and the solvent is then removed under reduced pressure. Thecrude product is dissolved in ethyl acetate and purified on silica gel(mobile phase: cyclohexane/ethyl acetate 9:1). This gives 1.6 g (39% oftheory).

LC-MS (method C): R_(t)=4.27 min

MS (ESIpos): m/z=255 (M+H)⁺

¹H-NMR (300 MHz, acetone-d₆): δ=0.85 (d, 3 H), 0.97 (d, 3H), 2.04 (m,1H), 2.81 (s, 3H), 3.25 (m, 1H), 3.42 (dd, 1H), 3.58 (m, 1H), 6.96 (s,1H), 7.02 (s, 1H).

Step d):

Ethyl 2-methylphenoxyacetate

10.81 g (0.10 mol) of 2-methylphenol and 13.82 g (0.10 mol) of potassiumcarbonate are suspended in 100 ml of N,N-dimethylformamide and stirredat 50° C. for 1 hour. 18.37 g (0.11 mol) of ethyl bromoacetate are thenadded dropwise and the mixture is stirred at 50° C. overnight. Aftercooling to room temperature, the mixture is concentrated under reducedpressure, taken up in ethyl acetate and washed three times with water.The organic phase is dried over sodium sulphate and the solvent isremoved under reduced pressure. Kugelrohr distillation of the residuegives 18.5 g (95% of theory) of the desired product.

GC-MS: R_(t)=12.50 min.

MS (ESIpos): m/z=194 (M)⁺

¹H-NMR (300 MHz, CDCl₃): δ=1.29 (t, 3H), 2.29 (s, 3H), 4.26 (q, 2H),4.62 (s, 2H), 6.70 (d, 1H), 6.89 (dt, 1H), 7.22 (t, 1H), 7.25 (d, 1H).

Step e):

Ethyl [4-(chlorosulphonyl)-2-methylphenoxy]acetate

110 g (0.5 mol) of ethyl (2-methylphenoxy)acetate are initially chargedin 250 ml of chloroform and cooled to 0° C. 330 g (2.8 mol) ofchlorosulphonic acid are slowly added dropwise to the solution. Thereaction mixture is stirred at RT for four hours and then poured ontoice and extracted three times with dichloromethane. The organic phase iswashed twice with water, once with saturated sodium bicarbonate solutionand once with saturated sodium chloride solution. The mixture is driedover sodium sulphate and the solvent is then removed under reducedpressure. This gives 153 g (93% of theory).

LC-MS (method C): R_(t)=3.95 min

MS (ESIpos): m/z=293 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃): δ=1.31 (t, 3H), 2.36 (s, 3H), 4.28 (q, 2H),4.75 (s, 2H), 6.81 (m, 2H), 7.85 (m, 2H).

Step f):

Ethyl{4-[(5-bromo-3-isopropyl-7-methyl-2,3-dihydro-1H-indol-1-yl)sulphonyl]-2-methylphenoxy}acetate

2.5 g (9.8 mmol) of 5-bromo-3-isopropyl-7-methylindoline are dissolvedin 20 ml of tetrahydrofuran, and 3 ml (21 mmol) of triethylamine, 20 mg(0.16 mmol) of DMAP and 2.8 g (9.8 mmol) of ethyl[4-(chlorosulphonyl)-2-methylphenoxy]acetate are added. The reactionmixture is stirred at RT overnight. The mixture is filtered and thesolvent is then removed under reduced pressure and the crude product ispurified on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1).This gives 4.8 g (96% of theory).

LC-MS (method B): R_(t)=3.29 min

MS (ESIpos): m/z=510 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃): δ=0.62 (d, 3H), 0.82 (d, 3H), 1.29 (t, 3H),1.84 (m, 1H), 2.22 (s, 3H), 2.27 (m, 1H), 2.51 (s, 3H), 3.56 (dd, 1H),3.95 (dd, 1H), 4.27 (q, 2H), 4.68 (s, 2H), 6.62 (m, 1H), 6.69 (s, 1H),7.25 (s, 1H), 7.30 (m, 2H).

Step g):

[4-({3-Isopropyl-7-methyl-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indol-1yl]-sulphonyl)-2-methylphenoxy]aceticacid

0.1 g (0.19 mmol) of ethyl{4-[(5-bromo-3-isopropyl-7-methyl-2,3-dihydro-1H-indol-1-yl)sulphonyl]-2-methylphenoxy}acetateis dissolved in 6 ml of absolute dimethylformamide, and 7 mg (0.01 mmol)of bis(triphenylphosphine)palladium(II) chloride and 48.3 mg (0.25 mmol)of 4-trifluoromethylphenylboronic acid are added under argon. Themixture is stirred at 70° C. for 30 minutes, and 1 ml of a 2 M solutionof sodium carbonate is then added. The reaction mixture is heated at100° C. for 16 h. After cooling to RT, the mixture is filtered throughsilica gel. The solvent is removed under reduced pressure and the crudeproduct is purified by preparative HPLC (YMC gel ODS-AQ S 5/15 μm;mobile phase A: water, mobile phase B: acetonitrile, gradient 0 min 30%B, 5 min 30% B, 50 min 95% B). This gives 65 mg (60% of theory).

LC-MS (method B): R_(t)=3.25 min

MS (ESIpos): m/z=548 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃): δ=0.80 (d, 3H), 1.86 (m, 1H), 2.22 (s, 3H),2.31 (m, 1H), 2.50 (s, 3H), 3.58 (dd, 1H), 3.95 (dd, 1H), 4.69 (s, 2H),6.59 (m, 1H), 6.69 (s, 1H), 7.28 (s, 1H), 7.33 (m, 2H).

Example 2[2-Methyl-4-({2,3,7-trimethyl-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indol-1-yl}sulphonyl)phenoxy]aceticacid

Step a):

5-Bromo-2,3,7-trimethyl-1H-indole

8 g (39.8 mmol) of 1-(4-bromo-2-methylphenyl)hydrazine (Example 1/stepa) are suspended in 14 ml of ethanol, and 3.7 g (52 mmol) of ethylmethyl ketone are added. After 30 minutes of stirring at RT, the solventis removed under reduced pressure and the intermediate is, withoutfurther purification, melted at 170° C. with 5.9 g (43 mmol) ofanhydrous zinc chloride. After 30-45 min, the melt is cooled to RT,taken up in dichloromethane and extracted with dilute hydrochloric acidand water. The organic phase is dried over magnesium sulphate and thesolvent is removed under reduced pressure. The crude product isdissolved in ethyl acetate and purified on silica gel (mobile phase:cyclohexane/ethyl acetate 9:1). This gives 3.8 g (40% of theory).

LC-MS (method D): R_(t)=4.92 min

MS (ESIpos): m/z=238 (M+H)⁺

¹H-NMR (300 MHz, acetone-d₆): δ=2.24 (s, 3H), 2.43 (s, 3H), 2.52 (s,3H), 7.03 (s, 1H), 7.45 (s, 1H), 9.96 (s, 1H).

Step b):

5-Bromo-2,3,7-trimethylindoline

3.8 g (15.8 mmol) of 5-bromo-3,7-dimethyl-1H-indole are dissolved in 30ml of glacial acetic acid and, at RT, 5 g (80 mmol) of sodiumcyanoborohydride are added a little at a time. The reaction mixture iswarmed at 35° C. for 16 hours and then hydrolysed with water andextracted twice with ethyl acetate. After drying over sodium sulphate,the solvent is removed under reduced pressure. The crude product isdissolved in ethyl acetate and purified on silica gel (mobile phase:cyclohexane/ethyl acetate 9:1). This gives 1.4 g (37% of theory).

LC-MS (method B): R_(t)=2.66 min

MS (ESIpos): m/z=240 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃): δ=1.26 (d, 3 H), 1.32 (d, 3H), 2.08 (s, 3H),2.85 (m, 1H), 3.48 (m, 1H), 6.98 (s, 2H).

Step c):

Ethyl{4-[(5-bromo-2,3,7-trimethyl-2,3-dihydro-1H-indol-1-yl)sulphonyl]-2-methyl-phenoxy}acetate

1.3 g (5.7 mmol) of 5-bromo-2,3,7-trimethylindoline are dissolved in 4ml of tetrahydrofuran, and 1.7 ml (12.5 mmol) of triethylamine, 20 mg(0.16 mmol) of DMAP and 1.6 g (5.7 mmol) of ethyl[4-(chlorosulphonyl)-2-methylphenoxy]acetate (Example 1/step e) areadded. The reaction mixture is stirred at RT overnight. Followingfiltration, the solvent is removed under reduced pressure and the crudeproduct is purified on silica gel (mobile phase: cyclohexane/ethylacetate 9:1). This gives 0.6 g (23% of theory).

LC-MS (method B): R_(t)=3.15 min

MS (ESIpos): m/z=496 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃): δ=0.56 (d, 3H), 1.23 (d, 3H), 1.27 (t, 3H),2.25 (s, 3H), 2.49 (m, 4H), 3.98 (m, 1H), 4.23 (q, 2H), 4.63 (s, 2H),6.64 (d, 1H), 7.00 (m, 1H), 7.23 (m, 1H), 7.39 (m, 2H).

Step d):

[2-Methyl-4-({2,3,7-trimethyl-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indol-1-yl}sulphonyl)phenoxy]aceticacid

0.08 g (0.16 mmol) of ethyl{4-[(5-bromo-2,3,7-trimethyl-2,3-dihydro-1H-indol-1-yl)sulphonyl]-2-methylphenoxy}acetateis dissolved in 6 ml of absolute dimethylformamide, and 7 mg (0.01 mmol)of bis(triphenylphosphine)palladium(II) chloride and 40 mg (0.21 mmol)of 4-trifluoromethylphenylboronic acid are added under argon. Themixture is stirred at 70° C. for 30 minutes, and 1 ml of a 2 M solutionof sodium carbonate is then added. The reaction mixture is heated at100° C. for 16 h. After cooling to RT, the mixture is filtered throughsilica gel. The solvent is removed under reduced pressure and the crudeproduct is purified by preparative HPLC (YMC gel ODS-AQ S 5/15 μm;mobile phase A: water, mobile phase B: acetonitrile, gradient 0 min 30%B, 5 min 30% B, 50 min 95% B). This gives 64 mg (74% of theory).

LC-MS (method C): R_(t)=5.26 min

MS (ESIpos): m/z=534 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃): δ=0.61 (d, 3H), 0.8 (d, 3H), 2.61 (s, 3H), 3.57(m, 1H), 3.78 (s, 2H), 3.91 (m, 1H), 6.51 (d, 1H), 6.90 (d, 2H), 6.98(s, 1H), 7.18 (d, 2H), 7.40 (m, 3H).

Example 3[4-({3,7-Dimethyl-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indol-1-yl}-sulphonyl)-2-methylphenoxy]aceticacid

Step a):

5-Bromo-3,7-dimethyl-1H-indole

5 g (24.8 mmol) of 1-(4-bromo-2-methylphenyl)hydrazine (Example 1/stepa) are suspended in 14 ml of ethanol, and 1.8 g (32 mmol) ofpropionaldehyde are added. The mixture is stirred at RT for 30 minutesand the solvent is then removed under reduced pressure and theintermediate is, without further purification, melted at 170° C. with3.7 g (27 mmol) of anhydrous zinc chloride. After 30-45 min, the melt iscooled to RT, taken up in dichloromethane and extracted with dilutehydrochloric acid and water. The organic phase is dried over magnesiumsulphate and the solvent is removed under reduced pressure. The crudeproduct is dissolved in ethyl acetate and purified on silica gel (mobilephase: cyclohexane/ethyl acetate 9:1). This gives 1.5 g (27% of theory).

LC-MS (method C): R_(t)=4.65 min

MS (ESIpos): m/z=224 (M+H)⁺

¹H-NMR (300 MHz, acetone-d₆): δ=2.26 (s, 3H), 2.48 (s, 3H), 7.06 (s,1H), 7.12 (s, 1H), 7.51 (s, 1H).

Step b):

5-Bromo-3,7-dimethylindoline

1.4 g (6.4 mmol) of 5-bromo-3,7-dimethyl-1H-indole are dissolved in 30ml of glacial acetic acid, and 2 g (33 mmol) of sodium cyanoborohydrideare added a little at a time at RT. The reaction mixture is warmed at35° C. for 16 hours and then hydrolysed with water and extracted twicewith ethyl acetate. After drying over sodium sulphate, the solvent isremoved under reduced pressure. The crude product is dissolved in ethylacetate and purified on silica gel (mobile phase: cyclohexane/ethylacetate 9:1). This gives 0.79 g (53% of theory).

LC-MS (method B): R_(t)=2.38 min

MS (ESIpos): m/z=227 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃): δ=1.29 (d, 3H), 2.09 (s, 3H), 3.13 (t, 1H),3.36 (m, 1H), 3.72 (t, 1H), 6.99 (s, 1H), 7.03 (s, 1H).

Step c):

Ethyl{4-[(5-bromo-3,7-dimethyl-2,3-dihydro-1H-indol-1-yl)sulphonyl]-2-methyl-phenoxy}acetate

0.7 g (3.4 mmol) of 5-bromo-3,7-dimethylindoline is dissolved in 4 ml oftetrahydrofuran, and 1 ml (7.4 mmol) of triethylamine, 20 mg of DMAP and1 g (3.4 mmol) of ethyl [4-(chlorosulphonyl)-2-methylphenoxy]acetate(Example 1/step e) are added. The reaction mixture is stirred at RTovernight. Following filtration, the solvent is removed under reducedpressure and the crude product is purified on silica gel (mobile phase:cyclohexane/ethyl acetate 9:1). This gives 1.5 g (90% of theory).

LC-MS (method D): R_(t)=5.25 min

MS (ESIpos): m/z=482 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃): δ=0.98 (d, 3H), 1.28 (t, 3H), 2.22 (s, 3H),2.39 (m, 1H), 2.52 (s, 3H), 3.31 (dd, 1H), 4.14 (dd, 1H), 4.27 (q, 2H),4.66 (s, 2H), 6.61 (d, 1H), 6.93 (s, 1H), 7.26 (m, 3H).

Step d):

[4-({3,7-Dimethyl-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indol-1-yl}-sulphonyl)-2-methylphenoxy]aceticacid

0.1 g (0.2 mmol) of ethyl{4-[(5-bromo-3,7-dimethyl-2,3-dihydro-1H-indol-1-yl)-sulphonyl]-2-methylphenoxy}acetateis dissolved in 6 ml of absolute dimethylformamide, and 7 mg (0.01 mmol)of bis(triphenylphosphine)palladium(II) chloride and 51 mg (0.26 mmol)of 4-trifluoromethylphenylboronic acid are added under argon. Themixture is stirred at 70° C. for 30 minutes, and 1 ml of a 2 M solutionof sodium carbonate is then added. The reaction mixture is heated at100° C. for 16 h. After cooling to RT, the mixture is filtered throughsilica gel. The solvent is removed under reduced pressure and the crudeproduct is purified by preparative HPLC (YMC gel ODS-AQ S 5/15 μm;mobile phase A: water, mobile phase B: acetonitrile, gradient 0 min 30%B, 5 min 30% B, 50 min 95% B). This gives 87 mg (81% of theory).

LC-MS (method D): R_(t)=5.18 min

MS (ESIpos): m/z=520 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃): δ=0.98 (d, 3H), 2.24 (s, 3H), 2.41 (m, 1H),2.53 (s, 3H), 3.31 (dd, 1H), 4.15 (dd, 1H), 4.66 (s, 2H), 6.63 (d, 1H),6.93 (s, 1H), 7.27 (m, 3H).

Example 4[4-({3-Isopropyl-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl}sulphonyl)-2-methylphenoxy]aceticacid

Step a):

5-Chloro-3-isopropyl-1H-pyrrolo[3,2-b]pyridine

0.2 g (1.39 mmol) of 2-chloro-5-hydrazinopyridine (prepared according toGB-259 961 from 5-amino-2-chloropyridine) is dissolved in ethanol, and0.16 g (1.8 mmol) of 3-methylbutanal is added. The mixture is stirred atRT for 30 minutes and the solvent is then removed under reduced pressureand the residue is dried under reduced pressure. 0.2 g (1.53 mmol) ofanhydrous zinc chloride is then added to the intermediate and themixture is heated in an oil bath at 170° C. After 30 minutes of stirringat this temperature, the mixture is cooled to RT. The crude product istaken up in dichloromethane and washed with dilute hydrochloric acid.After drying over magnesium sulphate, the solvent is removed underreduced pressure and the crude product is purified on silica gel (mobilephase: cyclohexane/ethyl acetate 1:1). This gives 133 mg (49% oftheory).

LC-MS (method B): R_(t)=2.62 min

MS (ESIpos): m/z=195 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃): δ=1.36 (d, 6H), 3.41 (m, 1H), 7.09 (d, 1H),7.22 (s, 1H), 7.58 (d, 1H).

Step b):

3-Isopropyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrrolo[3,2-b]pyridine

Under argon, 0.1 g (0.51 mmol) of5-chloro-3-isopropyl-1H-pyrrolo[3,2-b]pyridine, 0.13 g (0.67 mmol) of4-trifluoromethylphenylboronic acid and 0.018 g (0.026 mmol) ofbis(triphenylphosphine)palladium(II) chloride are initially charged in 6ml of DMF and heated at 70° C. for 30 minutes. After addition of 1 ml ofa 2 M solution of sodium carbonate, the reaction mixture is heated at100° C. overnight. After cooling, the mixture is filtered through silicagel. The solvent is removed under reduced pressure and the crude productis purified by preparative HPLC (YMC gel ODS-AQ S 5/15 μm; mobile phaseA: water, mobile phase B: acetonitrile, gradient 0 min 30% B, 5 min 30%B, 50 min 95% B). This gives 100 mg (64% of theory).

LC-MS (method C): R_(t)=4.47 min

MS (ESIpos): m/z=305 (M+H)⁺

Step c):

3-Isopropyl-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

0.085 g (0.279 mmol) of3-isopropyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrrolo-[3,2-b]pyridine and0.16 g (2.7 mmol) of Raney nickel are initially charged in 10 ml ofdecalin and hydrogenated at 80 bar and 180° C. for 16 h. The product isextracted with methanol and used without further purification for thenext reaction step.

LC-MS (method D): R_(t)=5.00 min

MS (ESIpos): m/z=307 (M+H)⁺.

Step d):

Ethyl[4-({3-isopropyl-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl}sulphonyl)-2-methylphenoxy]acetate

0.085 mg (0.277 mmol) of3-isopropyl-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-b]pyridineare dissolved in 2 ml of absolute THF, and 0.081 g (0.277 mmol) of ethyl[4-(chlorosulphonyl)-2-methylphenoxy]acetate (Example 1/step e) and0.085 ml (0.61 mmol) of triethylamine and 4 mg (0.028 mmol) of DMAP areadded. The reaction mixture is warmed at 45° C. overnight. The mixtureis then filtered and the solvent is removed under reduced pressure. Thecrude product is purified by preparative HPLC (YMC gel ODS-AQ S 5/15 μm;mobile phase A: water, mobile phase B: acetonitrile, gradient 0 min 30%B, 5 min 30% B, 50 min 95% B). This gives 37 mg (24% of theory).

LC-MS (method E): R_(t)=4.78 min

MS (ESIpos): m/z=563 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=0.82 (d, 3H), 1.06 (d, 3H), 1.45 (m, 1H),2.21 (m, 1H), 2.33 (s, 3H), 3.91 (m, 1H), 4.15 (m, 1H), 4.67 (s, 2H),7.04 (d, 1H), 7.92 (m, 5H), 7.99 (d, 2H), 8.34 (d, 2H).

Step e):

[4-({3-Isopropyl-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl}sulphonyl)-2-methylphenoxy]aceticacid

0.029 g (0.052 mmol) of ethyl[4-({3-isopropyl-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl}sulphonyl)-2-methylphenoxy]acetateis dissolved in 1 ml of THF, and 0.5 ml of 1 N aqueous sodium hydroxidesolution is added. The reaction mixture is stirred at RT overnight. Themixture is acidified with concentrated hydrochloric acid and thenextracted with dichloromethane. The extract is dried over magnesiumsulphate and the solvent is removed under reduced pressure. This gives27 mg (97% of theory).

LC-MS (method E): R_(t)=4.43 min

MS (ESIpos): m/z=535 (M+H)⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=0.82 (d, 3H), 1.06 (d, 3H), 1.45 (m, 1H),2.21 (m, 1H), 2.33 (s, 3H), 3.91 (m, 1H), 4.15 (m, 1H), 4.67 (s, 2H),7.04 (d, 1H), 7.92 (m, 5H), 7.99 (d, 2H), 8.34 (d, 2H).

Example 5(4-{[5-(4-Trifluoromethylphenyl)-2,3-dihydro-3-spiro-1′-cyclohexyl-1H-indol-1-yl]-sulphonyl}-2-methylphenoxy)aceticacid

Step a):

4-Bromophenylhydrazine hydrochloride

With stirring, a solution of 32.0 g (186 mmol) of 4-bromoaniline in 200ml of concentrated hydrochloric acid is cooled to 0° C. At thistemperature, a solution of 12.8 g (186 mmol) of sodium nitrite in 150 mlof water is added. The resulting diazonium solution is, with stirring at0-4° C., added dropwise to a solution of 42.7 g (225 mmol) of tin(II)chloride in 100 ml of concentrated hydrochloric acid. The resultingprecipitate is filtered off with suction and washed twice with in eachcase 50 ml of water and then recrystallized from isopropanol. This gives17.2 g (41% of theory) of the product as a solid.

R_(f) (dichloromethane/methanol 40:1)=0.46

UV [nm]=198, 234, 284

MS (ESIpos): m/z=187, 189 [M+H]⁺

¹H-NMR (DMSO-d₆, 300 MHz): δ=6.93 (2H, d), 7.46 (2H, d), 8.39 (1H, s,br.), 10.23 (3H, s, br.).

Step b):

5-Bromo-2,3-dihydro-3-spiro-1′-cyclohexyl-1H-indole

A mixture of 90 ml of toluene/acetonitrile (49:1) is flushed with argonfor 5 minutes, and 6.00 g (26.8 mmol) of 4-bromophenylhydrazinehydrochloride are then added. 7.41 ml (96.2 mmol) of trifluoroaceticacid are then slowly added dropwise, while care is being taken that thetemperature does not exceed 35° C. The temperature is then maintained at35° C., and a solution of 3.27 g (29.2 mmol) of cyclohexanecarbaldehydein 8.4 ml of toluene/acetonitrile (49:1) is then slowly added dropwiseover a period of 2 h. The mixture is stirred at 35° C. for 4 h and atroom temperature for 2 h. The mixture is then cooled to −10° C. and 8.0ml of methanol are added. Over a period of 30 min, 1.64 mg (43.3 mmol)of solid sodium borohydride is added a little at a time; during theaddition, the temperature must not exceed −2° C. After the addition hasended, the mixture is stirred at 0° C. for 1 h. 150 ml of a 6% strengthby weight solution of ammonia in water are added and the phases are thenseparated and 3 ml each of acetonitrile and methanol are then added tothe organic phase. The organic phase is then washed with 150 ml of a 15%strength solution of sodium chloride in water and dried over sodiumsulphate. The organic phase is filtered through 150 g of silica gel andthe filtercake is washed twice with in each case 200 ml of diethylether. The organic filtrate is concentrated under reduced pressure andchromatographed on 200 g of silica gel (70-230 mesh). First, thebyproducts are eluted using cyclohexane, and the product is then elutedusing a mixture of cyclohexane and diethyl ether (20:1). This gives 4.25g (50% of theory) of a solid.

R_(f) (petroleum ether/ethyl acetate 5:1)=0.4

MS (ESIpos): m/z=266, 268 [M+H]⁺

UV [nm]=200, 270, 276

¹H-NMR (DMSO-d₆, 400 MHz): δ=1.20-1.69 (10H, m), 3.30 (2H, d), 5.65 (1H,s), 6.39 (1H, d), 7.01 (1H, dd), 7.07 (1H, d).

Step c):

Ethyl{4-[(5-bromo-2,3-dihydro-3-spiro-1′-cyclohexyl-1H-indol-1-yl)sulphonyl]-2-methylphenoxy}acetate

A solution of 4.5 g (16.9 mmol) of5-bromo-2,3-dihydro-3-spiro-1′-cyclohexyl-1H-indole, 5.18 ml (37.2 mmol)of triethylamine and 210 mg (1.69 mmol) of 4-dimethylaminopyridine in 60ml of absolute tetrahydrofuran is cooled to −5° C., and a solution of4.95 g (16.91 mmol) of ethyl[4-(chlorosulphonyl)-2-methylphenoxy]-acetate (Example 1/step e) in 40ml of abs. tetrahydrofuran is added dropwise at this temperature. Themixture is stirred at room temperature for 18 h, and 150 ml of distilledwater are then added. The mixture is extracted three times with in eachcase 150 ml of ethyl acetate. The combined organic phases are washedwith 200 ml of saturated sodium chloride solution, dried over sodiumsulphate and concentrated under reduced pressure. The crude product ispurified by flash chromatography using 150 g of silica gel (70-230mesh). The mobile phase used is a mixture of cyclohexane and ethylacetate (6:1). This gives 8.25 g (93% of theory) of the product as asolid foam.

R_(f) (petroleum ether/ethyl acetate 3:1)=0.6

MS (ESIpos): m/z=508, 510 [M+H]⁺

UV [nm]=202, 238, 258

¹H-NMR (DMSO-d₆, 300 MHz): δ=1.16 (3H, t), 1.05-1.55 (10H, m), 2.20 (3H,s), 3.67 (2H, s), 4.13 (2H, q), 4.89 (2H, s), 7.00 (1H, dd), 7.34-7.42(3H, m), 7.55 (1H, dd), 7.68 (1H, d).

Step d):

{4-[(5-Bromo-2,3-dihydro-3-spiro-1′-cyclohexyl-1H-indol-1-yl)sulphonyl]-2-methyl-phenoxy}aceticacid

A solution of 0.53 g (9.47 mmol) of potassium hydroxide in 8 ml of wateris added to a solution of 3.3 g (6.32 mmol) of ethyl{4-[(5-bromo-2,3-dihydro-3-spiro-1′-cyclohexyl-1H-indol-1-yl)sulphonyl]-2-methylphenoxy}acetatein 16 ml of tetrahydrofuran. The mixture is stirred at room temperaturefor one hour, and 0.49 g (3.16 mmol) of sodium dihydrogen phosphatedihydrate is then added. The tetrahydrofuran is removed under reducedpressure and the residue is diluted with 40 ml of water. The mixture iswashed once with 40 ml of diethyl ether. The aqueous phase is adjustedto pH 2 using 1 N hydrochloric acid and extracted three times with ineach case 40 ml of dichloromethane. The organic phase is dried oversodium sulphate and concentrated under reduced pressure. This gives 2.55g (82% of theory) of the product as a solid foam.

R^(f) (petroleum ether/ethyl acetate 1:3)=0.14

MS (ESIpos): m/z=494, 496 [M+H]⁺

UV [nm]=206, 238, 258

¹H-NMR (DMSO-d₆, 200 MHz): δ=1.09-1.76 (10H, m), 2.19 (3H, s), 3.78 (2H,s), 4.78 (2H, s), 6.96 (1H, d), 7.37 (3H, d), 7.60 (1H, dd), 7.68 (1H,s), 13.2 (1H, s, br.).

Step e):

(4-{[5-(4-Trifluoromethylphenyl)-2,3-dihydro-3-spiro-1′-cyclohexyl-1H-indol-1-yl]-sulphonyl}-2-methylphenoxy)aceticacid

Under an atmosphere of argon, a solution of 170 mg (0.34 mmol) of{4-[(5-bromo-2,3-dihydro-3-spiro-1′-cyclohexyl-1H-indol-1-yl)sulphonyl]-2-methylphenoxy}aceticacid and 6.2 mg (8.5 μmol) of1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride in 3 ml of1,2-dimethoxyethane is added to 84.9 mg (0.45 mmol) of4-trifluoromethylboronic acid. With vigorous stirring, 0.76 ml of a 2 Nsolution of sodium carbonate are added. The mixture is stirred at 60° C.overnight. At room temperature, 8.50 mg (0.048 mmol) of1,3,5-triazine-2,4,6-trithiol are added to the reaction solution. The pHis adjusted to 4-5 using 5 N trifluoroacetic acid in water and thesolvent is then removed under reduced pressure. The residue is purifiedby RP-HPLC (Kroma-Sil 50×20 mm, mobile phase A: water with 0.3%trifluoroacetic acid, mobile phase B: acetonitrile, 0 min A:B=1:1, 7 minA:B=1:4, 8 min A:B=1:9). This gives 116 mg (61% of theory) of a solid.

R_(f) (methylene chloride/methanol 10:1)=0.28

MS (ESIpos): m/z=560 [M+H]⁺

UV [nm]=200, 292

¹H-NMR (DMSO-d₆, 200 MHz): δ=1.09-1.55 (10H, m), 2.20 (3H, s), 3.83 (2H,s), 4.79 (2H, s), 6.97 (1H, d), 7.57-7.88 (9H, m), 13.11 (1H, s).

Example 6(4-{[5-(4-Methoxyphenyl)-2,3-dihydro-1H-indol-1-yl]sulphonyl}-2-methylphenoxy)-aceticacid

Step a):

Ethyl{4-[(5-bromo-2,3-dihydro-1H-indol-1-yl)sulphonyl]-2-methylphenoxy}acetate

At a temperature of from −5 to 0° C., a solution of 1.17 g (4.00 mmol)of ethyl [4-(chlorosulphonyl)-2-methylphenoxy]acetate (Example 1/step e)in 8 ml of tetrahydrofuran is added dropwise to a solution of 792 mg(4.00 mmol) of 5-bromoindoline, 1.23 ml (8.80 mmol) of triethylamine and48.9 mg (0.400 mmol) of 4-dimethylaminopyridine in 12 ml oftetrahydrofuran. The mixture is allowed to warm to room temperature andstirred for a further 2 h. 30 ml of water are added to the reactionsolution, which is extracted three times with in each case 20 ml ofethyl acetate. The combined organic phases are dried with sodiumsulphate and the solvent is removed under reduced pressure. This gives1.5 g of crude product which is purified by flash chromatography (silicagel 70-230 mesh, mobile phase: cyclohexane/ethyl acetate 5:1). Thisgives 1.26 g (69% of theory) of the product as a solid.

R_(f) (petroleum ether/ethyl acetate 4:1)=0.25

MS (ESIpos): m/z=454 [M+H]⁺

UV [nm]=200, 208, 240

¹H-NMR (DMSO-d₆, 200 MHz): δ=1.17 (3H, t), 2.20 (3H, s), 2.93 (2H, t),3.88 (2H, t), 4.14 (2H, q), 4.90 (2H, s), 7.00 (1H, d), 7.35-7.42 (3Hm), 7.58-7.65 (2H, m).

Step b):

4-[(5-Bromo-2,3-dihydro-1H-indol-1-yl)sulphonyl]-2-methylphenoxyaceticacid

A solution of 57.4 mg (1.02 mmol) of potassium hydroxide in 1 ml ofwater is added to a solution of 310 mg (0.682 mmol) of ethyl{4-[(5-bromo-2,3-dihydro-1H-indol-1-yl)sulphonyl]-2-methylphenoxy}acetatein 2 ml of tetrahydrofuran. The mixture is stirred at room temperaturefor 45 minutes and the solvent is then removed under reduced pressure.The residue is diluted with 3 ml of water and adjusted to pH 2 using 1 Nhydrochloric acid. The resulting precipitate is filtered off withsuction through a filter cartridge. The precipitate is washed twice within each case 2 ml of water and dried under reduced pressure. This gives279 mg (96% of theory) of the product as a solid.

MS (ESIpos): m/z=426, 428 [M+H]⁺

UV [nm]=200, 238

¹H-NMR (DMSO-d₆, 300 MHz): δ=2.19 (3H, s), 2.93 (2H, t), 3.89 (2H, t),4.79 (2H, s), 6.97 (1H, d), 7.31-7.41 (3H, m), 7.57-7.65 (2H, m).

Step c):

(4-{[5-(4-Methoxyphenyl)-2,3-dihydro-1H-indol-1-yl]sulphonyl}-2-methylphenoxy)-aceticacid

Under an atmosphere of argon, 54.7 mg (0.360 mmol) of4-methoxyphenylboronic acid and 33.6 mg (0.792 mmol) of lithium chlorideare initially charged. A solution of 128 mg (0.300 mmol) of4-[(5-bromo-2,3-dihydro-1H-indol-1-yl)sulphonyl]-2-methylphenoxyaceticacid and 3.5 mg (3.0 μmol) of tetrakis(triphenylphosphine)-palladium(0)in 3 ml of 1,2-dimethoxyethane is added. With vigorous stirring, 660 μlof a 2 M solution of sodium carbonate in water are added. The mixture isheated at 60° C. overnight and then allowed to cool to room temperature.8.50 mg (0.048 mmol) of 1,3,5-triazine-2,4,6-trithiol and 9.0 mg (0.041mmol) of 2,2-bis(hydroxymethyl)-2,2′,2″-nitrilotriethanol are added tothe reaction solution, and the mixture is concentrated under reducedpressure. The residue is washed with 2 ml of a solvent mixture ofcyclohexane/ethyl acetate (2:1), taken up in a mixture of 3 ml of1,2-dimethoxyethane and 0.6 ml of water and acidified with 0.66 ml of 5N trifluoroacetic acid (pH≦4). The solvent is removed under reducedpressure and the residue is taken up in tetrahydrofuran and purified bypreparative RP-HPLC (Kroma-Sil 50×20 mm, mobile phase A: water with 0.3%trifluoroacetic acid, mobile phase B: acetonitrile, 0 min A:B=9:1, 2 minA:B=9:1, 7 min A:B=1:9, 8 min A:B=1:9). This gives 107 mg (79% oftheory) of the product as a lyophilisate.

MS (ESIpos): m/z=454 [M+H]⁺

UV [nm]=204, 246, 280

¹H-NMR (DMSO-d₆, 300 MHz): δ=2.19 (3H, s), 2.97 (2H, t), 3.77 (3H, s),3.91 (2H, t), 4.78 (2H, s), 6.97 (3H, d), 7.39-7.53 (5H, m), 7.62-7.64(2H, m).

Example 7(4-{[5-(4-Trifluoromethylphenyl)-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl]sulphonyl}-2-methylphenoxy)aceticacid

Step a):

5-Bromo-3,3-dimethylindoline

A mixture of 45 ml of toluene/acetonitrile (49:1) is flushed with argonfor 5 minutes, and 3.00 g (13.4 mmol) of 4-bromophenylhydrazine are thenadded. 3.71 ml (48.1 mmol) of trifluoroacetic acid are then addedslowly, while care is being taken that the temperature does not exceed35° C. The temperature is then maintained at 35° C., and a solution of1.05 g (14.6 mmol) of isobutyraldehyde in 4 ml of toluene/acetonitrile(49:1) is then slowly added dropwise over a period of 2 h. The mixtureis stirred at 35° C. for 4 h and at room temperature for 2 h. Themixture is then cooled to −10° C., 4.0 ml of methanol are added and 819mg (21.7 mmol) of solid sodium borohydride are then added a little at atime over a period of 30 min. Here, the temperature must not exceed −2°C. After the addition has ended, the mixture is stirred at 0° C. for 1h. 150 ml of a 6% strength by weight solution of ammonia in water areadded, the phases are then separated and 1.5 ml each of acetonitrile andmethanol are added to the organic phase. The organic phase is thenwashed with 150 ml of a 15% strength solution of sodium chloride inwater and dried over sodium sulphate. The mixture is filtered through100 g of silica gel, and the filter cake is washed twice with in eachcase 200 ml of diethyl ether. The organic filtrate is concentrated underreduced pressure and chromatographed on 100 g of silica gel. Initially,the byproducts are eluted with cyclohexane, and the product is theneluted using a mixture of cyclohexane/diethyl ether (20:1). This gives1.78 g (54% of theory) of the product as an oil.

R_(f) (petroleum ether/ethyl acetate 5:1)=0.47

UV [nm]=200, 268, 276

MS (ESIpos): m/z=226 [M+H]⁺

¹H-NMR (DMSO-d₆, 200 MHz): δ=1.20 (6H, s), 3.18 (2H, d), 5.66 (1H, s,br.), 6.42 (1H, d), 7.02 (1H, dd), 7.10 (1H, d).

Step b):

Ethyl{4-[(5-bromo-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)sulphonyl]-2-methyl-phenoxy}acetate

A solution of 920 mg (4.07 mmol) of 5-bromo-3,3-dimethylindoline, 906 mg(8.95 mmol) of triethylamine and 49.7 mg (0.407 mmol) of4-dimethylaminopyridine in 12.5 ml of absolute tetrahydrofuran is cooledto −5° C., and a solution of 1.19 g (4.07 mmol) of ethyl[4-(chlorosulphonyl)-2-methylphenoxy]acetate (Example 1/step e) in 10 mlof abs. tetrahydrofuran is added dropwise at this temperature. Themixture is stirred at room temperature for 18 h, and 100 ml of distilledwater are then added. The mixture is extracted three times with in eachcase 50 ml of ethyl acetate. The combined organic phases are washed with200 ml of saturated sodium chloride solution, dried over sodium sulphateand concentrated under reduced pressure. The crude product is purifiedby flash chromatography using 150 g of silica gel. This gives 1.74 g(89% of theory) of the product as a solid foam.

R_(f) (petroleum ether/ethyl acetate 3:1)=0.48

LC-MS (method A): R_(f)=5.18 min

MS (ESIpos): m/z=482 [M+H]⁺

UV [nm]=200, 238, 256

Step c):

{4-[(5-Bromo-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)sulphonyl]-2-methylphenoxy}-aceticacid

A solution of 173 mg (3.08 mmol) of potassium hydroxide and 2.5 ml ofwater is added to a solution of 990 mg (2.05 mmol) of ethyl{4-[(5-bromo-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)sulphonyl]-2-methylphenoxy}acetatein 5 ml of tetrahydrofuran, and the mixture is stirred at RT for 45 min.160 mg (1.03 mmol) of sodium dihydrogen phosphate dihydrate are added.The solvent is removed under reduced pressure. 40 ml of water are addedto the residue, and the mixture is washed with 20 ml of diethyl ether.The pH is then adjusted to 2 using a 1 N solution of hydrochloric acid,and the mixture is extracted three times with in each case 20 ml ofdichloromethane. The organic phases are dried over sodium sulphate andthe solvent is then removed under reduced pressure. This gives 805 mg(86% of theory) of the product as a solid foam.

R_(f) (dichloromethane/methanol 10:1)=0.31

MS (ESIpos): m/z=454, 456 [M+H]⁺

¹H-NMR (DMSO-d₆, 300 MHz): δ=1.10 (6H, s), 2.21 (3H, s), 3.64 (2H, s),4.79 (2H, s), 6.99 (1H, d), 7.33-7.41 (3H, m), 7.62 (1H, dd), 7.65 (1H,s), 13.05 (1H, s, br.).

Step d):

(4-{[5-(4-Trifluoromethylphenyl)-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl]sulphonyl}-2-methylphenoxy)aceticacid

Under argon, a solution of 77.2 mg (0.17 mmol) of{4-[(5-bromo-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)sulphonyl]-2-methylphenoxy}aceticacid and 6.2 mg (8.5 μmol) of1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride in 1.5 ml of1,2-dimethoxyethane is added to 38.0 g (0.20 mmol) of4-trifluoromethylphenylboronic acid. With vigorous stirring, 374 μl of a2 M solution of sodium carbonate in water are then added, and themixture is stirred at 60° C. under argon for 17 h. To remove thepalladium, 8.50 mg (0.048 mmol) of 1,3,5-triazine-2,4,6-trithiol areadded to the reaction mixture, and the mixture is neutralized using 5 Ntrifluoroacetic acid in water. The mixture is concentrated under reducedpressure and the residue is taken up in 3 ml of a mixture ofdichloromethane and methanol (5:1) and filtered through a cartridgefilled with 2 g of silica gel. The product is eluted with 20 ml of thedichloromethane/methanol mixture (5:1) and the solvent is removed underreduced pressure. The residue is dissolved in a mixture of 400 μl oftetrahydrofuran and 200 μl of dimethyl sulphoxide and chromatographed byreversed-phase HPLC (Kroma-Sil, 50×20 mm, mobile phase A: water, mobilephase B: acetonitrile with 0.3% trifluoroacetic acid, gradient 0 min 50%A, 50% B; 7 min 20% A and 80% B; 8 min 10% A and 90% B). The solvent isremoved under reduced pressure. This gives 46.1 mg (52% of theory) ofthe product as a solid.

LC-MS (method A): R_(t)=5.15 min

MS (ESIpos): m/z=520 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 MHz): δ=1.19 (6H, s), 2.21 (3H, s), 3.70 (2H, s),4.79 (2H, s), 6.99 (1H, d), 7.52-7.62 (3H, m), 7.67 (1H, d), 7.71 (1H,s), 7.76 (2H, d), 7.85 (2H, d).

The working examples 8-96 listed in the table below are obtainedanalogously to the processes described above: LC- MS: LC- MW Ex.Synthesis R₁ MS found No. method Structure [min] method [M + H]⁺ 8Analogous to Example 1

3.27 B 562 9 Analogous to Example 1

3.08 B 523 10 Analogous to Example 1

3.21 B 508 11 Analogous to Example 1

3.25 B 578 12 Analogous to Example 1

3.17 B 512 13 Analogous to Example 1

3.12 B 524 14 Analogous to Example 1

3.03 B 510 15 Analogous to Example 1

3.16 B 494 16 Analogous to Example 1

3.14 B 498 17 Analogous to Example 1

3.09 B 516 18 Analogous to Example 5

5.10 D 465 19 Analogous to Example 5

5.40 D 545 20 Analogous to Example 5

5.19 D 501 21 Analogous to Example 5

5.20 D 535 22 Analogous to Example 5

5.50 D 507 23 Analogous to Example 5

4.77 D 481 24 Analogous to Example 5

5.36 D 519 25 Analogous to Example 5

5.10 D 519 26 Analogous to Example 5

4.94 D 487 27 Analogous to Example 5

4.85 D 451 28 Analogous to Example 5

4.86 D 487 29 Analogous to Example 5

4.97 D 487 30 Analogous to Example 5

4.89 D 469 31 Analogous to Example 5

5.10 D 485 32 Analogous to Example 5

5.31 D 499 33 Analogous to Example 5

5.10 D 483 34 Analogous to Example 5

4.83 D 469 35 Analogous to Example 5

5.25 D 557 36 Analogous to Example 5

5.00 D 497 37 Analogous to Example 5

5.31 D 527 38 Analogous to Example 5

4.99 D 495 39 Analogous to Example 5

4.79 D 481 40 Analogous to Example 5

4.73 D 476 41 Analogous to Example 5

5.49 C 575 42 Analogous to Example 5

5.09 C 521 43 Analogous to Example 5

5.30 C 527 44 Analogous to Example 5

5.26 D 527 45 Analogous to Example 5

5.39 C 559 46 Analogous to Example 5

5.09 C 521 47 Analogous to Example 5

5.18 C 491 48 Analogous to Example 5

5.04 C 535 49 Analogous to Example 5

5.82 C 547 50 Analogous to Example 5

4.98 D 534 51 Analogous to Example 5

4.95 C 516 52 Analogous to Example 5

5.20 C 527 53 Analogous to Example 5

5.68 C 585 54 Analogous to Example 5

5.68 C 539 55 Analogous to Example 5

5.45 C 544 56 Analogous to Example 5

5.48 C 519 57 Analogous to Example 5

5.39 D 523 58 Analogous to Example 5

5.53 D 597 59 Analogous to Example 5

5.33 F 537 60 Analogous to Example 5

4.47 F 535 61 Analogous to Example 5

5.45 C 525 62 Analogous to Example 5

5.31 C 526 63 Analogous to Example 5

4.43 F 539 64 Analogous to Example 5

5.63 C 583 65 Analogous to Example 5

4.45 F 509 66 Analogous to Example 1

5.26 E 534 67 Analogous to Example 1

5.18 E 480 68 Analogous to Example 1

5.32 E 550 69 Analogous to Example 1

4.84 E 496 70 Analogous to Example 1

4.99 E 484 71 Analogous to Example 1

4.88 E 496 72 Analogous to Example 1

5.66 E 522 73 Analogous to Example 1

5.03 E 502 74 Analogous to Example 5

5.72 E 588 75 Analogous to Example 5

5.79 E 604 76 Analogous to Example 5

5.38 E 550 77 Analogous to Example 5

5.44 E 538 78 Analogous to Example 5

5.32 E 550 79 Analogous to Example 5

5.69 E 534 80 Analogous to Example 5

3.27 B 590 81 Analogous to Example 5

3.25 B 532 82 Analogous to Example 5

3.24 B 574 83 Analogous to Example 5

3.05 B 536 84 Analogous to Example 5

3.22 B 520 85 Analogous to Example 5

3.05 B 536 86 Analogous to Example 1

5.5 E 562 87 Analogous to Example 1

4.16 E 507 88 Analogous to Example 1

5.55 D 508 89 Analogous to Example 1

5.4 E 548 90 Analogous to Example 1

3.43 B 536 91 Analogous to Example 1

5.4 E 508 92 Analogous to Example 1

4.95 C 485 93 Analogous to Example 1

5.2 C 480 94 Analogous to Example 1

5.4 E 494 95 Analogous to Example 1

5.3 E 512 96 Analogous to Example 1

4.92 C 496

Example A

Cellular Transactivation Assay:

Test Principle:

A cellular assay is used to identify activators of the peroxisomeproliferator-activated receptor delta (PPAR-delta).

Since mammalian cells contain different endogenous nuclear receptorswhich may complicate an unambiguous interpretation of the results, anestablished chimera system is used in which the ligand binding domain ofthe human PPARδ receptor is fused to the DNA binding domain of the yeasttranscription factor GAL4. The resulting GAL4-PPARδ chimera isco-transfected and stably expressed in CHO cells having a reporterconstruct.

Cloning:

The GAL4-PPARδ expression construct contains the ligand binding domainof PPARδ (amino acids 414-1326), which is PCR-amplified and cloned intothe vector pcDNA3.1. This vector already contains the GAL4 DNA bindingdomain (amino acids 1-147) of the vector pFC2-dbd (Stratagene). Thereporter construct, which contains five copies of the GAL4 binding siteupstream of a thymidine kinase promoter, expresses firefly luciferase(Photinus pyralis) following activation and binding of GAL4-PPARδ.

Transactivation Assay (Luciferase Reporter):

CHO (chinese hamster ovary) cells are sown in CHO-A-SFM medium (GIBCO),supplemented by 2.5% foetal calf serum and 1% penicillin/streptomycin(GIBCO), at a cell density of 2×10³ cells per well in a 384-well plate(Greiner). The cells are cultivated at 37° C. for 48 h and thenstimulated. To this end, the substances to be tested are taken up in theabovementioned medium and added to the cells. After a stimulation periodof 24 hours, the luciferase activity is measured using a video camera.The relative light units measured give, as a function of the substanceconcentration, a sigmoidal stimulation curve. The EC₅₀ values arecalculated using the computer program GraphPad PRISM (Version 3.02).

In this test, Working Examples 1-96 show EC₅₀ values in a range of from1 to 200 nM.

Example B Description of the Test for Finding Pharmacologically ActiveSubstances which Increase HDL Cholesterol (HDL-C) Concentrations in theSerum of Transgenic Mice Transfected with the Human ApoA1 Gene (hApoA1)and/or Have an Effect on the Metabolic Syndrome of Adipose ob,ob Miceand Lower Their Blood Glucose Concentration:

The substances to be examined in vivo for their HDL-C-increasingactivity are administered orally to male transgenic hApoA1 mice. One dayprior to the start of the experiment, the animals are randomized intogroups with the same number of animals, generally n=7-10. Throughout theexperiment, the animals have drinking water and feed ad libitum. Thesubstances are administered orally once a day for 7 days. To this end,the test substances are dissolved in a solution of Solutol HS15+ethanol+saline (0.9%) in a ratio of 1+1+8 or in a solution of SolutolHS 15+saline (0.9%) in a ratio of 2+8. The dissolved substances areadministered in a volume of 10 ml/kg of body weight using a stomachtube. Animals which have been treated in exactly the same manner buthave only been given the solvent (10 ml/kg of body weight), without testsubstance, serve as control group.

Prior to the first administration of substance, a blood sample from eachof the mice is taken by puncture of the retroorbital venous plexus, todetermine ApoA1, serum cholesterol, HDL-C and serum triglycerides (TG)(zero value). Subsequently, using a stomach tube, the test substance isadministered for the first time to the animals. 24 hours after the lastadministration of substance (i.e. on day 8 after the start of thetreatment), another blood sample is taken from each animal by punctureof the retroorbital venous plexus, to determine the same parameters. Theblood samples are centrifuged and, after the serum has been obtained,cholesterol and TG are determined photometrically using an EPOS Analyzer5060 (Eppendorf-Gerätebau, Netheler & Hinz GmbH, Hamburg). The saiddeterminations are carried out using commercial enzyme tests (BoehringerMannheim, Mannheim).

To determine the HDL-C, the non-HDL-C fraction is precipitated using 20%PEG 8000 in 0.2 M glycine buffer pH 10. From the supernatant, thecholesterol is determined UV-photometrically (BIO-TEK Instruments, USA)in a 96-well plate using a commercial reagent (Ecoline 25, Merck,Darmstadt).

Human mouse-ApoA1 is determined with a Sandwich ELISA method using apolyclonal anti-human-ApoA1 antibody and a monoclonal anti-human-ApoA1antibody (Biodesign International, USA). Quantification is carried outUV-photometrically (BIO-TEK Instruments, USA) using peroxidase-coupledanti-mouse-IGG antibodies (KPL, USA) and peroxidase substrate (KPL, USA)

The effect of the test substances on the HDL-C concentration isdetermined by subtracting the value measured for the 1st blood sample(zero value) from the value measured for the 2nd blood sample (after thetreatment). The mean of the differences of all HDL-C values of one groupis determined and compared to the mean of the differences of the controlgroup.

Statistical evaluation is carried out using Student's t-test, after thevariances have been checked for homogeneity.

Substances which increase the HDL-C of the treated animals in astatistically significant (p<0.05) manner by at least 15%, compared tothat of the control group, are considered to be pharmacologicallyeffective.

To examine substances for their effect on a metabolic syndrome, animalshaving an insulin resistance and increased blood glucose levels areused. To this end, C57B1/6J Lep <ob> mice are treated using the sameprotocol as for the transgenic ApoA1 mice. The serum lipids aredetermined as described above. In these animals, serum glucose isadditionally determined, as a parameter for blood glucose. Serum glucoseis determined enzymatically in an EPOS Analyzer 5060 (see above), usingcommercially available enzyme tests (Boehringer Mannheim).

A blood-glucose-lowering effect of the test substances is determined bysubtracting the value measured for the 1st blood sample of an animal(zero value) from the value measured for the 2nd blood sample of thesame animal (after the treatment). The mean of the differences of allserum glucose values of one group is determined and compared to the meanof the differences of the control group.

Statistical evaluation is carried out using Student's t-test, after thevariances have been checked for homogeneity.

Substances which lower the serum glucose concentration of the treatedanimals in a statistically significant (p<0.05) manner by at least 10%,compared to the control group, are considered to be pharmacologicallyeffective.

1. A compound of formula (I)

in which A represents the group C—R¹¹ or represents N, where R¹¹represents hydrogen or (C₁-C₄)-alkyl, X represents O, S or CH₂, R¹represents (C₆-C₁₀)-aryl or represents 5- to 10-membered heteroarylhaving up to three heteroatoms selected from the group consisting of N,O and S, which radicals may for their part each be mono- totrisubstituted by identical or different substituents selected from thegroup consisting of halogen, cyano, nitro, (C₁-C₆)-alkyl (which for itspart may be substituted by hydroxyl), (C₁-C₆)-alkoxy, phenoxy,benzyloxy, trifluoromethyl, trifluoromethoxy, (C₂-C₆)-alkenyl, phenyl,benzyl, (C₁-C₆)-alkylthio, (C₁-C₆)-alkylsulphonyl, (C₁-C₆)-alkanoyl,(C₁-C₆)-alkoxycarbonyl, carboxyl, amino, (C₁-C₆)-acylamino, mono- anddi-(C₁-C₆)-alkylamino and 5- or 6-membered heterocyclyl having up to twoheteroatoms from the group consisting of N, O and S, or represents agroup of the formula

R² and R³ are identical or different and independently of one anotherrepresent hydrogen or (C₁-C₆)-alkyl or together with the carbon atom towhich they are attached form a 3- to 7-membered spiro-linked cycloalkylring, R⁴ represents hydrogen or (C₁-C₆)-alkyl, R⁵ represents hydrogen or(C₁-C₆)-alkyl, R⁶ represents hydrogen or (C₁-C₆)-alkyl, R⁷ representshydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or halogen, R⁸ and R⁹ areidentical or different and independently of one another representhydrogen or (C₁-C₄)-alkyl, and R¹⁰ represents hydrogen or represents ahydrolysable group which can be degraded to the corresponding carboxylicacid, or a pharmaceutically acceptable salt, solvate, or solvate of asalt thereof.
 2. The compound of formula (I) according to claim 1, inwhich A represents the group C—R¹¹ or represents N, where R¹¹ representshydrogen or methyl, X represents O or S, R¹ represents phenyl orrepresents 5- or 6-membered heteroaryl having up to two heteroatomsselected from the group consisting of N, O and S, which radicals may fortheir part each be mono- or disubstituted by identical or differentsubstituents selected from the group consisting of fluorine, chlorine,cyano, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, phenoxy, benzyloxy,trifluoromethyl, trifluoromethoxy, vinyl, phenyl, benzyl, methylthio,methylsulphonyl, acetyl, propionyl, (C₁-C₄)-alkoxycarbonyl, amino,acetylamino, mono- and di-(C₁-C₄)-alkylamino, R² and R³ are identical ordifferent and independently of one another represent hydrogen or(C₁-C₄)-alkyl or together with the carbon atom to which they areattached form a 5- or 6-membered spiro-linked cycloalkyl ring, R⁴represents hydrogen or methyl, R⁵ represents hydrogen, or methyl, R⁶represents hydrogen or methyl, R⁷ represents hydrogen, (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, fluorine or chlorine, R⁸ and R⁹ are identical ordifferent and independently of one another represent hydrogen or methyl,and R¹⁰ represents hydrogen.
 3. The compound of formula (I) according toclaim 1, in which A represents CH or N, X represents O, R¹ representsphenyl or pyridyl which for their part may each be mono- ordisubstituted by identical or different substituents selected from thegroup consisting of fluorine, chlorine, methyl, tert-butyl, methoxy,trifluoromethyl, trifluoromethoxy, methylthio, amino and dimethylamino,R² represents hydrogen or methyl, R³ represents methyl, isopropyl ortert-butyl, or R² and R³ together with the carbon atom to which they areattached form a spiro-linked cyclohexane ring, R⁴ represents hydrogen ormethyl, R⁵ represents hydrogen, methyl or ethyl, R⁶ represents hydrogenor methyl, R⁷ represents methyl, R⁸ and R⁹ each represent hydrogen, andR¹⁰ represents hydrogen.
 4. A compound of the formula (I-A)

in which R² represents hydrogen, R³ represents methyl, isopropyl ortert-butyl, or R² and R³ both represent methyl or together with thecarbon atom to which they are attached form a spiro-linked cyclohexanering, and A, R¹, R⁴, R⁵ and R⁶ are each as defined in claim
 1. 5. Aprocess for preparing the compounds of formula (I) or (I-A) as definedin claims 1 and 4 respectively, characterized in that a compound offormula (II)

in which A, R², R³, R⁴ and R⁵ are each as defined in claim 1 and Yrepresents chlorine or bromine, is initially converted using a compoundof formula (III)

in which X, R⁶, R⁷, R⁸ and R⁹ are each as defined in claim 1 and Trepresents benzyl or (C₁-C₆)-alkyl, in an inert solvent in the presenceof a base into a compound of formula (IV)

in which A, T, X, Y, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each asdefined in claim 1, this compound is then reacted in a coupling reactionwith a compound of formula (V)

in which R¹ is as defined in claim 1 and R¹² represents hydrogen ormethyl or both radicals together form a —CH₂CH₂— or —C(CH₃)₂—C(CH₃)₂—bridge, in an inert solvent in the presence of a suitable palladiumcatalyst and a base to give a compound of formula (I-B)

in which A, T, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each asdefined in claim 1, the compound (I-B) is then reacted with acid or baseor, if T represents benzyl, also hydrogenolytically, to give thecorresponding carboxylic acid of formula (I-C)

in which A, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each as definedin claim 1, and the carboxylic acid (I-C) is, if appropriate, furthermodified by known esterification methods to give the compound of formula(I).
 6. (cancelled)
 7. A pharmaceutical composition, comprising at leastone compound of the formula (I) or (I-A) as defined in claims 1 and 4,respectively, and an inert non-toxic pharmaceutically acceptablecarrier, auxiliary, solvent, vehicle, emulsifier, or dispersant. 8.(cancelled)
 9. (cancelled)
 10. A method for the prevention and treatmentof stroke, arteriosclerosis, coronary heart diseases and dyslipidaemias,for the prophylaxis of myocardial infarction and for the treatment ofrestenosis after coronary angioplasty or stenting comprisingadministering to a mammal an effective amount of a compound of formula(I) or formula (IV) as defined in claim 1 and 4, respectively. 11.(cancelled)